# Patent

## Title
Cyclosporin derivatives and uses thereof

## Abstract

The present invention relates to a compound of the Formula (I)):




or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, and hair loss.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This patent application is a continuation-in-part of International Application No. PCT/US2011/063295, filed Dec. 5, 2011, which claims priority to U.S. Application Ser. No. 61/419,326, filed Dec. 3, 2010; this patent application also claims priority to U.S. Application Ser. Nos. 61/655,236, filed Jun. 4, 2012; 61/684,928, filed Aug. 20, 2012; and the entire contents of each of the foregoing applications are hereby incorporated by reference herein.


FIELD OF THE INVENTION
The invention relates to novel cyclosporine derivatives, their pharmaceutical compositions comprising the same, and methods for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, and hair loss.
BACKGROUND OF THE INVENTION
Cyclosporins in nature are poly-N-methyl, cyclic undecapeptides, isolated from fungi. Cyclosporin A has an immunosuppressive activity and has been used for almost 30 years to prevent rejection in kidney, heart and liver transplant recipients. It possesses anti-inflammatory properties and has been used for treating severe rheumatoid arthritis, severe psoriasis, Behget's uveitis, and dry eye disease. In addition, it is useful for treating severe ulcerative colitis, Crohn's disease, alopecia greata, aplastic anemia, HSV-1 stromal keratitis, systemic lupus erythematosus, and severe lupus nephritis. However, its strong immunosuppressive activity limits its applications in many diseases.
The anti-HIV activity of cyclosporin A was first discovered in 1986 and has been continually studied since then (Klatzmann, D., et al., 1986, C R Acad. Sci. III, 303(9):343-8; Wainberg, M. A., et al., 1988, Blood, 72, 1904-10; Luban, J., et al., 1993, Cell, 73, 1067-1078; each of which is incorporated herein by reference). Its non-immunosuppressive derivative, NIM-811, was reported to have potent anti HIV activity due to its ability to inhibit cyclophilin A (Franke, E. K., et al., 1994, Nature, 372, 359-362; Thali, M., et al., 1994, Nature, 372, 363-365; Gamble, T. R., et al., 1996, Cell, 87, 1157-1159; Rosenwirth B., et al., 1994, Antimicrob. Agents Chemother., 38, 1763-1772; each of which is incorporated herein by reference).
Cyclosporin A and its non-immunosuppressive derivatives, as such as NIM-811 (N-MeIle-4-Cyclosporin), Debio-025, and SCY-635, bind and inhibit cyclophilins; cyclophilins interact with HCV protein NS5A and NS5B and stimulate its RNA-binding activity. As a result, these compounds have an effective anti-HCV activity (Watashi, K., et al., 2007, Rev. Med. Virol., 17:245-252.37; Inoue, K., et al., 2001, Nippon Rinsho., 59, 1326-30; Inoue, K., et al., 2003, J. Gastroenterol., 38, 567-72; Watashi, K., et al., 2003, Hepatology, 38, 1282-8; Gaither, L. A., et al., 2010, Virology, 397, 43-55; each of which is incorporated herein by reference). Currently, NIM-811, Debio-025, and SCY-635 are undergoing clinical trials for treating HCV.
NIM-811 and Debio-025 have a chemical structure similar to cyclosporine A and possess a poor pharmacokinetic profile. In addition, they are metabolized by P450 for inducing drug interactions (Lill, J., et al., 2000, Am J Health-Syst Pharm 57, 1579; incorporated herein by reference).
SCY-635 has an improved pharmacokinetic profile and low blood serum binding. In addition, it has a low potential for drug-drug interactions. SCY-635's in vitro anti-HCV activity (EC50) was reported to be 0.10 μM (Hopkins, S. et al., 2010, Antimicrob. Agents Chemother., 54, 660-672, incorporated herein by reference). However, SCY-635 is not chemically stable, as it is easily converted to its diastereoisomer by epimerization. Its diastereoisomer is expected to have poor binding activity with cyclophilins, and as a result, its anti-viral activity in vivo may be affected (See, e.g., WO2012/009715, WO2012/021796, and WO2012/075494, each of which incorporated herein by reference in its entirety).
Cyclosporin A and its non-immunosuppressive derivatives were also found to possess anti-HBV activity through the inhibition of cyclophilins (Chokshi, S., et al., 2012, Gut 61:A11; Chokshi, S., et al., 2012, Poster Presentations, 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012), Barcelona, Spain; Chokshi, S., et al., 2011, Abstract 190 (Poster Presentations), 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011), Berlin, March 30-April 3; Tian, X. C., et al., 2010, J. Virol., 84, 3373-3381; Xia, W. L., et al., 2004, Hepatobiliary Pancreat Dis Int., 4, 18-22; Michael, J., et al., 2003, J. Virol., 77, 7713-7719; each of which is incorporated herein by reference).
Furthermore, cyclophilins were reported to regulate the life cycle and pathogenesis of several viruses, including severe acute respiratory syndrome coronavirus, vaccinia virus, and herpes simplex virus (Castro, A. P., et al., 2003, J. Virol., 77, 9052-9068; Chen, Z., L., et al., 2005, J. Infect. Dis. 191(5):755-760; Arai, C., et al., Nihon Rinsho Meneki Gakkai Kaishi., 35(1), 87-91; Labetoulle, M., 2012, J Fr Ophtalmol., 35(4), 292-307; De Clercq, E., 2008, Expert Opin Emerg Drugs., 13(3):393-416; Vahlne, A., 1992, Arch Virol., 122(1-2):61-75; each of which is incorporated herein by reference). Cyclosporin A and its non-immunosuppressive derivatives also possess such anti viral-activities.
N-MeVal-4-Cyclosporin (SDZ 220-384), another non-immunosuppressive cyclosporine derivative, was reported to have similar biological activities to that of NIM-811 (Fliri, H., et al., 1993, Ann. N Y Acad Sci. 696, 47-53; Zenke, G., et al., 1993, Ann N Y Acad Sci. 23; 685:330-5).
Hepatitis C virus (HCV) is a small (55-65 nm in size), enveloped, positive sense single strand RNA virus in the Flaviviridae family. HCV has a high rate of replication and an exceptionally high mutation rate. About 80% of people infected with HCV develop chronic, persistent infection. More than 4 million Americans have been infected with HCV and more than 200 million people are estimated to be infected chronically worldwide. About 35,000 new cases of hepatitis C are estimated to occur in the United States each year. HCV infection is responsible for about 50% of all chronic liver disease, 30% of all liver transplants, and 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The peg-interferon and ribavirin combination is the standard treatment for chronic hepatitis C, but it has low efficacy against HCV infection. Recently, the FDA has approved Vertex's Incivek (telaprevir) and Merck's Victrelis (boceprevir) as an add-on to the current interferon/ribavirin therapy for treating HCV. Both drugs are HCV protease inhibitors that target the virus to prevent its replication. However, due to HCV's fast mutation rate, drug resistance can be developed in a short period of time. Thus, there exists a need for an effective therapeutic for HCV treatment.
Hepatitis B virus (HBV) is a 42 nm partially double stranded DNA virus composed of a 27 nm nucleocapsid core (HBcAg) that is surrounded by an outer lipoprotein envelope containing the surface antigen (HBsAg). More than 2 billion people have been infected, and there are 350 million chronic carriers of the virus. The disease has caused epidemics in parts of Asia and Africa. Chronic hepatitis B will cause liver cirrhosis and liver cancer, a fatal disease with a very poor response to current chemotherapies. The infection is preventable by vaccination, and HBV load and replication can be reduced by current antiviral drugs, such as lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka), entecavir (Baraclude), and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys). However, none of the available drugs can clear the infection. There remains a need for an effective therapeutic to treat HBV infection.
The non-immunosuppressive cyclosporin derivatives bind to cyclophilins, a family of host proteins that catalyze cis-trans peptidyl-prolyl isomerization in protein folding and regulation, which are crucial for the processing and maturation of the viral proteins for viral replication. HIV and HCV are viruses with a high mutation rate. All current anti-viral drugs target the virus itself; when the virus mutates, it leads to the development of drug resistance. Instead of directly targeting the virus, targeting host cofactors (cyclophilins) will be slow down the development of drug resistance due to a higher genetic barrier (Rosenwirth, B., et al., 1994, Antimicrob. Agents Chemother., 38, 1763-1772; Tang, H. L. et al., 2010, Viruses, 2, 1621-1634; Hopkins, S. et al., 2010, Oral Presentation, Scynexis's SCY-635 Demonstrates Impressive Barrier to Resistance in HCV Treatment, the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010), Vienna, Austria, April 14-18; each of which is incorporated herein by reference). Cyclosporine derivatives affect a new target, cyclophilins, and therefore represent a new mechanism of action against viruses.
There are 17 cyclophilins in the human genome, but the functions of these cyclophilin isoforms are still unclear (Davis, T. L., et al., 2010, PLoS Biol. 8(7):e1000439; incorporated herein by reference). Cyclophilin A, B, C, D, and other such isoforms play an important role in the pathophysiology of a number of serious diseases, such as cancer (Campa, M J., et al., 2003, Cancer Res., 63(7), 1652-6; Li, M., et al., 2006, Cancer, 106: 2284-94; Yang, H., et al., 2007, Biochem Biophys Res Commun., 361(3):763-7; Obchoei, S., et al., 2009, Med Sci Monit., 15(11), RA221-32; Andersson, Y., et al., 2009, Br J Cancer, 101, 1307-1315; Lee, J., 2010, Arch Pharm Res., 33(2), 181-7; Lee, J., et al., 2010, J Exp Clin Cancer Res., 29:97; Obchoei, S., 2011, Molecular Cancer, 10:102; Takahashi, M., et al., 2012, Oncol Rep., 27(1):198-203; Qian, Z., et al., 2010, BMC Cancer, 12:442; each of which is incorporated herein by reference), inflammations (the result of interactions between a secreted extracellular cyclophilin and CD-147, a surface protein; Yurchenko V., 2005, Immunology, 117(3):301-9; Yurchenko, V., 2010, Clin Exp Immunol., 160(3):305-17; Malesevie, M., 2010, Angew Chem Int Ed Engl., 49(1):213-5; each of which is incorporated herein by reference), rheumatoid arthritis (Wells, G., et al., 2000, Cochrane Database Syst Rev., (2):CD001083; Kim, H., et al., 2005, Clin Immunol., 116(3):217-24; Yang, Y., Rheumatology (Oxford), 47(9):1299-310; Yurchenko, V., et al., 2006, Immunology, 117(3):301-9; Damsker, J. M., 2009, Immunology, 126(1):55-62; Wang, L., et al., 2010, J Clin Immunol., 30(1):24-33; Billich A., et al., 1997, J Exp Med., 185:975-80; De Ceuninck F., et al., 2003, Arthritis Rheum., 48:2197-206; each of which is incorporated herein by reference), respiratory inflammation (Foda, H. D., et al., 2001, Am J Respir Cell Mol Biol., 25:717-24; Hasaneen, N. A., et al., FASEB J., 19:1507-9. Yurchenko, V., et al., 2006, Immunology, 117(3):301-9; Gwinn, W. M., 2006, J Immunol., 177(7):4870-9; Onoue, S., 2009, J Control Release., 138(1):16-23; Balsley, M. A., et al., 2010, J Immunol., 185(12):7663-70; Balsley, M., et al., 2010, Am. J. Respir. Crit. Care Med., 181(1): A6821; Stemmy, E. J., et al., 2011, J. Asthma, 48(10):986-993; Stemmy, E. J., et al., 2011, Am J Respir Cell Mol Biol., 45(5):991-8; Amin, K., 2012, Respir Med., 106(1):9-14; Onoue, S., 2012, Eur J Pharm Biopharm., 80(1):54-60; each of which is incorporated herein by reference), lupus (Caccavo, D., et al., 1997, Arthritis & Rheumatism, 40(1):27-35; Dostál, C., et al., 1998, Lupus, 7(1):1 29-36; Tam, L S., et al., 1998, Q J Med., 91(8):573-580; Fu, L W., et al., 1998, Rheumatology 37 (2): 217-221; Hallegua, D., et al., 2009, Lupus, 9: 241-251; each of which is incorporated herein by reference), psoriasis (Ellis, C. N., 1991, N Engl J Med., 324, 277-284; Lebwohl, M., et al., 1998, J Am Acad Dermatol., 39(3):464-75; Rosmarin, D M., et al., 2010, J Am Acad Dermatol., 62(5):838-53; each of which is incorporated herein by reference), atopic dermatitis (Naeyaert, J. M., et al., 1999, Dermatology, 198:145-152; Pacor, M L., et al., 2001, Recenti Prog Med., 92(6):390-1; Ricci, G., et al., 2009, Drugs, 69(3):297-306; Simon, D., 2011, Curr Probl Dermatol., 41:156-64; each of which is incorporated herein by reference), dry eye disease (Pflugfelder, S. C., 2004, Am J Ophthalmol., 137(2), 337-42; Kymionis, G. D., et al 2008, Clin Ophthalmol., 2, 829-836; Kunert, K. S., et al., 2002, Arch Ophthalmol., 120, 330-7; Yavuz, B., et al., 2012, Scientific World Journal. 2012:194848; each of which is incorporated herein by reference), severe Graves' ophthalmopathy (Prummel, M. F., 1989, N Engl J Med., 321(20), 1353-9; incorporated herein by reference), endogenous uveitis (Nussenblatt, R. B., et al., 1991, Am J Ophthalmol., 112(2), 138-46; which is incorporated herein by reference), Wegener's granulomatosis (Georganas, C., et al., 1996, Clin Rheumatol., 15(2), 189-92; incorporated herein by reference), vernal keratoconjutivitis (Pucci, N., et al., 2002, Ann Allergy Asthma Immunol., 89, 298-303; incorporated herein by reference), atopic keratoconjutivitis (Akpek, E. K., et al., 2004, Ophthalmology, 111, 476-82; incorporated herein by reference), ligneous conjutivitis (Rubin, B. I., et al., 1991, Am J Ophthalmol., 112, 95-96; incorporated herein by reference), conjuctival linchen planus (Levell, N. J., et al., 1992, Br J Dermatol., 127, 66-7; incorporated herein by reference), and superior limbic keratoconjutivitis (Perry, H. D., et al., 2003, Ophthalmology, 110, 1578-81; incorporated herein by reference), inflammatory bowel disease-Crohn's Disease and Ulcerative Colitis (Sandborn, W. J., 1995, Inflamm Bowel Dis. 1:48-63; Shibolet, O., et al., 2005, Cochrane Database Syst Rev., (1):CD004277; Rufo, P. A., et al., 2006, Paediatr Drugs, 8(5):279-302; Reindl, W., et al., 2007, Gut., 56(7):1019; Hart, A. L., et al., 2010, Aliment Pharmacol Ther., 32(5):615-27; Cheifetz, A. S., et al., 2011, J Clin Gastroenterol., 45(2):107-12; Sharkey, L., 2011, J Crohns Colitis., 5(2):91-4; Fabro, M., et al., 2011, Curr Drug Targets., 12(10):1448-53; Van Assche, G., et al., 2011, Gut., 60(1):130-3; each of which is incorporated herein by reference), NSAID-induced enteropathy (LoGuidice, A., at al., 2010, Toxicol. Sci., 118, 276-285; which is incorporated herein by reference), cardiovascular diseases (including vascular stenosis, atherosclerosis, abdominal aortic aneurysms, aortic rupture, cardiac hypertrophy, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases; Jin, Z. G., et al., 2000, Circ Res., 87(9):789-96; Yurchenko, V., et al., 2005, Immunology, 117, 301-309; Suzuki, J., et al., 2006, Circ Res., 98(6):811-7; Satoh, K., et al., 2008, Circulation., 117(24):3088-98; Nishihara, M., et al., 2008, J Mol Cell Cardiol., 44(2):441-442; Satoh, K., et al., 2010, Circ J., 74(11):2249-56; Satoh, K., et al., 2010, Antioxid Redox Signal., 12(5):675-82; Hausenloy, D. J., et al., 2012, Br J Pharmacol. 165(5):1235-45; Coppinger, J. A., et al., 2004, Blood, 103(6):2096-104; Satoh, K., et al., 2010, Antioxid Redox Signal., 1:12(5), 675-682; Nigro, P., et al., 2010, J Exp Med., 208(1):53-66; Wang, W. L., et al., 2011, Med Hypotheses, 77(5):734-8; Hattori, F., 2012, J Mol Cell Cardiol., 53(1):1-2; Seizer P., 2012, J Mol Cell Cardiol., 53(1):6-14; each of which is incorporated herein by reference), and ischaemic brain diseases (Boulos, S., et al., 2007, Neurobiol Dis., 25:54-64; incorporated herein by reference).
Due to cyclophilin inhibition, cyclosporin derivatives also possess the following biological activities: anti-fungal (Kirkland, T. N., et al., 1983, Antimicrob Agents Chemother., 24(6): 921-924; Mody, C. H., et al., 1988, Infect Immun., 56(1): 7-12; Roilides, E., et al., 1994, Antimicrob Agents Chemother., 38(12): 2883-2888; Moussaff, M., et al., 1997, Appl Environ Microbiol., 63(5):1739-43; Cruz, M. C., et al., 2000, Antimicrob Agents Chemother., 44(1):143-9; each of which is incorporated herein by reference), anti-malarial (Nickell, S. P., et al., 1982, Infect Immun., 37(3):1093-100; Murphy, J. R., et al, 1988, Antimicrob Agents Chemother., 32(4):462-6; Marín-Menéndez, A., et al., 2012, Mol Biochem Parasitol., 184(1):44-7; each of which is incorporated herein by reference), and anti-parasitic (including Leishmania donovani, Cryptosporidium parvum, Hymenolepis nana, Toxoplasma, Trypanosoma cruzi, and Schistosome; Chappell, L. H., et al., 1992, Parasitology, 105 Suppl:S25-40; Bell, A., et al., 1996, Gen Pharmacol., 27(6):963-71; Yau, W. L., et al., 2010, PLoS Negl Trop Dis., 4(6):e729; Yurchenko, V., et al., 2008, Int J Parasitol., 38(6):633-9; Perkins, M. E., et al., 1998, Antimicrob Agents Chemother., 42(4):843-8; Matsuzawa, K., et al., 1998, Int J Parasitol., 28(4):579-88; Silverman, J. A., et al., 1997, Antimicrob Agents Chemother., 41(9):1859-66; Búa, J., et al., 2008, Parasitology, 135(2):217-28; Búa, J., et al., 2004, Bioorg Med Chem Lett., 14(18):4633-7; Bout, D. T, et al., 1984, Am J Trop Med. Hyg., 33(1):185-6; Bout, D., et al., 1986, Infect Immun., 52(3):823-7; Munro, G. H., et al., 1991, Parasitology, 102 Pt 1:57-63; each of which is incorporated herein by reference). In addition, cyclosporin derivatives can promote hair growth (Watanabe, S., et al., 1991, J Dermatol., (12):714-9; Paus R., et al., 1994, J Invest Dermatol., 103:2, 143-7; Hozumi, Y., et al., 1994, J Dermatol Sci., 7 Suppl: S33-8; Takahashi, T., et al., 2001, J Invest Dermatol., 117(3):605-11; Taylor M., et al., 1993, J Invest Dermatol., 100:3, 237-9; Gafter-Gvili, A., et al., 2004, Arch Dermatol Res., 296(6):265-9; each of which is incorporated herein by reference).
Recent research for Alzheimer's disease indicated that Cyclophilin A is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration (Bell, R. D., et al., 2012, Nature, 485(7399):512-6; Bell, R. D., et al., 2009, Acta Neuropathol., 118(1):103-13; each of which is incorporated herein by reference).
Due to the function of extracellular cyclophilins, it is necessary to emphasize that the special target of a secreted extracellular cyclophilin using a cell-impermeable derivative of cyclosporine will be very effective in reducing inflammation for diseases such as respiratory inflammation and cardiovascular diseases (Yurchenko V., 2005, Immunology, 117(3):301-9; Yurchenko, V., 2010, Clin Exp Immunol., 160(3):305-17; Malesević, M., 2010, Angew Chem Int Ed Engl., 49(1):213-5; Balsley, M. A., et al., 2010, J Immunol., 185(12):7663-70; Balsley, M., et al., 2010, Am. J. Respir. Crit. Care Med., 181(1): A6821; Satoh, K., et al., 2010, Circ J., 74(11):2249-56; each of which is incorporated herein by reference).
Cyclophilin D (CypD) is very important for mitochondrial related neuro and cardiovascular functions because it is an integral part of the mitochondrial permeability transition pore (mPTP). Unregulated opening of the mPTP can lead to mitochondrial swelling and cell death. Thus, the CypD-mediated mPTP is directly linked to a new pharmacologic treatment strategy for many neuro and cardiovascular diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS, aging, heart failure, traumatic brain injury, spinal cord injury, epilepticus, stroke, ischemia-reperfusion injury in the brain, heart, kidney, and particularly in myocardial infarction. The CypD-mediated mPTP is also linked to a new treatment strategy for cancer, obesity, diabetes, and muscular dystrophy (Henry-Mowatt, J., 2004, Oncogene, 23, 2850-60; Galluzzi, L., 2006, Oncogene, 25, 4812-4830; Hirai, K., et al., 2001, J Neurosci., 21, 3017-3023; Friberg, H., et al., 2002, Biochimie, 84, 241-250; Waldmeier, P. C., et al., 2003, Curr Med Chem., 10, 1485-506; Hansson, M. J., et al., 2004, J Bioenerg Biomembr., 36, 407-13; Sullivan, P. G., et al., 2005, J Neurosci Res., 79, 231-9; Baines, C. P., et al, 2005, Nature 434, 658-662; Shanmuganathan, S., et al, 2005, Am J Physiol Heart Circ Physiol., 289, H237-H242; McBride, H. M., et al., 2006, Curr Biol., 16, R551-560; Mandemakers, W., et al., 2007, J Cell Sci., 120, 1707-1716; Kroemer, G., et al., 2007, Physiol Rev., 87, 99-163; Ibarra, A., et al., 2007, Brain Res., 1149, 200-209; Michelakis, E. D., et al, 2008, Circulation, 117, 2431-2434; Du, H., et al, 2008, Nature Medicine, 14, 1097-1105; Piot C., et al., 2008, N Engl J Med., 359, 473-81; Hatton, J., et al., 2008, J Neurosurg., 109, 699-707; Tatsuta, T., et al., 2008, EMBO J, 27, 306-314; Reutenauer, J., et al., 2008, Br J Pharmacol., 155, 574-84; Mazzeo, A. T., et al., 2009, Exp Neurol., 218, 363-370; Galluzzi, L., et al, 2009, Nature Rev Neurosci., 10, 481-494; Halestrap, A. P., et al., 2009, Biochim Biophys Acta., 1787, 1402-15; Arnett, A. L. H., et al., 2009, Curr. Opin. Genet. Dev., 19, 290-297; Tiepolo, T., et al., 2009, Br J Pharmacol., 157, 1045-1052; Wissing, E. R., et al., 2010, Neuromuscul Disord., 20, 753-60; Halestrap, A. P., et al., 2010, Biochem Soc Trans., 38, 841-860; Cernak, I., et al., 2010, J Cereb Blood Flow Metab., 30, 255-66; Elrod, J. W., et al., 2010, J Clin Invest., 120, 3680-3687; Duchen, M. R., et al., 2010, Essays Biochem., 47, 115-37; Schapira, A. H. V., et al., 2011, Parkinson's Disease, Volume 2011, 1-7 Article ID 159160; Osman, M. M., et al., 2011, Neuropeptides, 45, 359-368; Devalaraja-Narashimha K., et al., 2011, FEES Lett., 585, 677-82; Fujimoto, K., et al., 2010, Proc Natl Acad Sci USA. 107, 10214-9; Irwin, W. A., et al., 2003, Nat Genet., 35, 267-271; Angelin, A., et al., 2007, Proc Natl Acad Sci USA, 104, 991-6; Merlini, L., et al., 2008, Proc Natl Acad Sci USA, 105, 5225-9; Millay, D. P., 2008, Nat Med., 14, 442-7; each of which is incorporated herein by reference). Cyclosporine A and its derivatives can block CypD to prevent mitochondrial swelling and cell death, and therefore could be useful for treatment of the aforementioned diseases, for example, as a neuro and cardiovascular protective agent or as a novel mitochondrial medicine.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of Formula (I):




or pharmaceutically acceptable salt thereof, wherein:

    R8 is n-butyl, (E)-but-2-enyl, or






     —(CH2)4—SR9, —(CH2)4—(C═O)OR9, or —(CH2)3—(C═O)OR9;
    each occurrence of R9 is independently hydrogen or (C1-C6)alkyl;
    R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
    W is O, S, CH2 or NR1;
    R1 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle; or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    R3 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl;






and

    each R5 is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl.


In another aspect, the present invention provides a compound of Formula (I) as shown above, or pharmaceutically acceptable salt thereof, wherein:

    R8 is n-butyl, (E)-but-2-enyl, or






     —(CH2)4—SR9, —(CH2)4—(C═O)OR9, or —(CH2)3—(C═O)OR9;
    each occurrence of R9 is independently hydrogen or (C1-C6)alkyl;
    R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
    W is O, S, CH2, or NR1;
    R1 is hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    R3 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl;
    
    
    R7 is






    R5 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRC(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    p is an integer of 0, 1, 2, 3, 4, or 5; and
    m is an integer of 1, 2, 3, 4 or 5.


In another aspect, the present invention provides a compound of Formula (I) as shown above, or pharmaceutically acceptable salt thereof, wherein:

    R8 is n-butyl, (E)-but-2-enyl, or






     —(CH2)4—SR9, —(CH2)4—(C═O)OR9, or —(CH2)3—(C═O)OR9;
    each occurrence of R9 is independently hydrogen or (C1-C6)alkyl;
    R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
    W is O, S, CH2, or NR1;
    R1 is hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    R3 is:
    
        H;
        (C7-C12)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C7-C12)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; or
        (C7-C12)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
    
    
    R7 is






    R5 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRC(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, (C3-C7)cycloalkyl, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    p is an integer of 0, 1, 2, 3, 4, or 5; and
    m is an integer of 1, 2, 3, 4 or 5.


In another aspect, the present invention provides a compound of Formulae (II) through (VI):







or pharmaceutically acceptable salt thereof, wherein:

 represents a single bond or double bond;

each W is independently O, S, CH2, or NR1;

each R1 is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle; or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; and

each occurrence of R3 and R5 is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl.

In another aspect, the present invention provides a compound of Formulae (II) through (VI): as shown above, or pharmaceutically acceptable salt thereof, wherein:

    each W is independently O, S, CH2 or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
        or RA and RB, together with the nitrogen atom to which they are attached, form —N═CH—NRFRF′, —N═CMe-NRFRF′, or —NRFC(═NH)NRFRF′;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each occurrence of RF and RF′ is independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or RF and RF′, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    p is an integer of 0, 1, 2, 3, 4, 5, or 6;
    m is an integer of 1, 2, 3, 4, 5, or 6; and
    n is an integer of 1, 2, 3, 4, 5 or 6.


In another aspect, the present invention provides a compound of Formulae (II) through (VI) as shown above, or pharmaceutically acceptable salt thereof, wherein:

    each W is independently O, S, CH2 or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C7-C12)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C7-C12)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA; or
        (C7-C12)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; or
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, (C3-C7)cycloalkyl, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
        or RA and RB, together with the nitrogen atom to which they are attached, form —N═CH—NRFRF′, —N═CMe-NRFRF′, or —NRFC(═NH)NRFRF′;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, or C(═O)O(C1-C4)alkyl;
    each occurrence of RF and RF′ is independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or RF and RF′, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    p is an integer of 0, 1, 2, 3, 4, 5, or 6;
    m is an integer of 1, 2, 3, 4, 5, or 6; and
    n is an integer of 1, 2, 3, 4, 5 or 6.


In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound as described herein and a pharmaceutically-acceptable carrier.
In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
In another aspect, the present invention provides a method for treating or preventing hepatitis C virus infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
In yet another aspect, the present invention provides a method for inhibiting a cyclophilin in a subject in need thereof, which comprises administrating to said subject an effective cyclophilin-inhibiting amount of at least one compound as described herein.
In yet another aspect, the present invention provides a method for treating or preventing diseases that are mediated by cyclophilins in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's Diseases, and ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kidney.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from cardiovascular diseases, vascular stenosis, atherosclerosis, abdominal aortic aneurysms, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases.
In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from cancer, obesity, diabetes, muscular dystrophy, and hair loss.
In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from allergic conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, Behcet's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, corneal transplant rejection, corneal sensitivity impaired due to surgery on the cornea or other surface of the eye, meibomian gland disease, ptyregia, ocular symptoms of graft versus host disease, ocular allergy, ocular cicatricial pemphigoid, Steven Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, ocular rosacea, and Pinguecula.


DETAILED DESCRIPTION OF THE INVENTION
Definitions
The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.
The terms “alkyl” and “alk” refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “(C1-C4)alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. The term “(C1-C6)alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 6 carbon atoms, such as n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, in addition to those exemplified for “(C1-C4)alkyl.” “Substituted alkyl” refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substitutents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.
The term “alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplaries of such groups include ethenyl or allyl. The term “C2-C6 alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. “Substituted alkenyl” refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted.
The term “alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. An exemplary of such groups includes ethynyl. The term “C2-C6 alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl. “Substituted alkynyl” refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted.
The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. “C3-C7 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc, together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substitutents can themselves be optionally substituted.
The term “cycloalkenyl” refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplaries of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc, together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc, together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
The terms “heterocycle” and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term “heteroarylium” refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
“Substituted heterocycle” and “substituted heterocyclic” (such as “substituted heteroaryl”) refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., ═O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
The term “alkylamino” refers to a group having the structure —NHR′, wherein R′ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
The term “dialkylamino” refers to a group having the structure —NRR′, wherein R′ and R′ are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined herein. R and R′ may be the same or different in an dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R′ are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or nonaromatic. Examples of cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.
The terms “halogen” or “halo” refer to chlorine, bromine, fluorine or iodine.
Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
The compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of a compound of the present invention may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Compounds of the present invention which contain an acidic moiety, such but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.
Compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to greater than 95%, equal to or greater than 99% pure (“substantially pure” compound I), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention.
All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.
Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.
Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.
Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders. The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
Compounds
The novel cyclosporin derivatives of the present invention are potent inhibitors of cyclophilins and are useful for inhibiting viruses such as HCV, HBV, and HIV.
In one aspect, the present invention provides a compound Formula (I):




or pharmaceutically acceptable salt thereof, wherein:

    R8 is n-butyl, (E)-but-2-enyl, or






     —(CH2)4—SR9, —(CH2)4—(C═O)OR9, or —(CH2)3—(C═O)OR9;
    each occurrence of R9 is independently hydrogen or (C1-C6)alkyl;
    R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
    W is O, S, CH2 or NR1;
    R1 is hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    R3 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl;
    
    
    R7 is






    R5 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRC(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    p is an integer of 0, 1, 2, 3, 4, or 5; and
    m is an integer of 1, 2, 3, 4 or 5.


In one aspect, the present invention provides a compound Formula (I):




or pharmaceutically acceptable salt thereof, wherein:

    R8 is n-butyl, (E)-but-2-enyl, or






     —(CH2)4—SR9, —(CH2)4—(C═O)OR9, or —(CH2)3—(C═O)OR9;
    each occurrence of R9 is independently hydrogen or (C1-C6)alkyl;
    R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
    W is O, S, CH2 or NR1;
    R1 is hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    R3 is:
    
        H;
        (C7-C12)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C7-C12)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; or
        (C7-C12)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
    
    
    R7 is






    R5 is:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRC(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, (C3-C7)cycloalkyl, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    p is an integer of 0, 1, 2, 3, 4, or 5; and
    m is an integer of 1, 2, 3, 4 or 5.


In certain embodiments, R3 is (C7-C10)alkyl. In certain other embodiments, R3 is (C7-C8)alkyl. In yet other embodiments, R3 is (C7-C12) linear alkyl. In yet other embodiments, R3 is (C7-C10) linear alkyl. In yet other embodiments, R3 is (C7-C8) linear alkyl.
In certain embodiments, R4 is hydroxyl. In certain other embodiments, R4 is C(═O)ORA.
In certain embodiments, R8 is n-butyl. In certain other embodiments, R8 is (E)-but-2-enyl. In certain other embodiments, R8 is




In yet other embodiments, R8 is —(CH2)4—SR9. In yet other embodiments, R8 is —(CH2)4—(C═O)OR9. In yet other embodiments, R8 is —(CH2)3—(C═O)OR9. In certain embodiments, each occurrence of R9 is independently hydrogen. In certain other embodiments, each occurrence of R9 is independently (C1-C6)alkyl. In certain embodiments, R2 is ethyl.

In certain embodiments, the compound of Formula I has the structure of Formulae (II) through (VI):







or pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each W is independently O, S, CH2, or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
        or RA and RB, together with the nitrogen atom to which they are attached, form —N═CH—NRFRF′, —N═CMe-NRFRF′, or —NRFC(═NH)NRFRF′;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each occurrence of RF and RF′ is independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or RF and RF′, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    p is an integer of 0, 1, 2, 3, 4, 5, or 6;
    m is an integer of 1, 2, 3, 4, 5, or 6; and
    n is an integer of 1, 2, 3, 4, 5 or 6.


In certain embodiments, the compound of Formula I has the structure of Formulae (II) through (VI):







or pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each W is independently O, S, CH2, or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C7-C12)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C7-C12)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA; or
        (C7-C12)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, (C3-C7)cycloalkyl, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
        or RA and RB, together with the nitrogen atom to which they are attached, form —N═CH—NRFRF′, —N═CMe-NRFRF′, or —NRFC(═NH)NRFRF′;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each occurrence of RF and RF′ is independently hydrogen, (C1-C6)alkyl, phenyl, benzyl, or RF and RF′, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    p is an integer of 0, 1, 2, 3, 4, 5, or 6;
    m is an integer of 1, 2, 3, 4, 5, or 6; and
    n is an integer of 1, 2, 3, 4, 5 or 6.


In certain embodiments, R3 is (C7-C10)alkyl. In certain other embodiments, R3 is (C7-C8)alkyl. In yet other embodiments, R3 is (C7-C12) linear alkyl. In yet other embodiments, R3 is (C7-C10) linear alkyl. In yet other embodiments, R3 is (C7-C8) linear alkyl.
In certain embodiments, R4 is hydroxyl. In certain other embodiments, R4 is C(═O)ORA.
In certain embodiments, W is O. In certain other embodiments, W is S. In yet other embodiments, W is NH. In yet other embodiments, W is CH2, yet other embodiments, W is NR1. In yet other embodiments, W is N—(C1-C4)alkyl.
In certain embodiments, m is 1. In certain other embodiments, m is 2. In yet other embodiments, m is 3. In yet other embodiments, m is 4 or 5.
In certain embodiments, p is 0. In certain other embodiments, p is 1. In yet other embodiments, m is 2. In yet other embodiments, m is 3, 4 or 5.
In certain embodiments, R3 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2CMe3, phenyl, CH2-phenyl,




In certain embodiments, R3 is —(CH2)nNRARB, wherein n is an integer of 2, 3, 4, 5 or 6, or integer of 7, 8, 9, 10, 11 or 12; and wherein each occurrence of RA and RB is independently hydrogen; (C1-C4)alkyl, optionally substituted by one or more groups RD which may be the same or different, in which each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl; or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (C1-C4)alkyl, phenyl and benzyl.
In certain embodiments, R3 is —(CH2)nNRARB, wherein n is an integer of 2, 3, 4, 5 or 6, or integer of 7, 8, 9, 10, 11 or 12; and wherein RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (C1-C4)alkyl, phenyl and benzyl.
In certain embodiments, n is 2. In certain other embodiments, n is 3. In yet other embodiments, n is 4, 5, or 6. In yet other embodiments, n is 7 or 8. In yet other embodiments, n is 9 or 10. In yet other embodiments, n is 11 or 12.
In certain embodiments, R3 is —(CH2)nNRARB, wherein n is an integer of 7, 8, 9, 10, 11 or 12; and wherein each occurrence of RA and RB is independently hydrogen; (C1-C4)alkyl, optionally substituted by one or more groups RD which may be the same or different, in which each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl; or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (C1-C4)alkyl, phenyl and benzyl.
In certain embodiments, n is 7. In certain other embodiments, n is 8. In yet other embodiments, n is 9, 10, 11 or 12.
In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or 3-dialkylaminopropyl, wherein said alkyl is (C1-C4)alkyl.
In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or 3-dialkylaminopropyl, wherein said alkyl is (C1-C4)alkyl, wherein R3 is dimethylaminoethyl, diethylaminoethyl, methylethylaminoethyl, methyl-iso-butylaminoethyl, ethyl-iso-butylaminoethyl, methyl-tert-butylaminoethyl, or ethyl-tert-butylaminoethyl.
In certain embodiments, R3 is







in which n is an integer of 2, 3, 4, 5, or 6, and m is an integer of 2, 3, or 4. In certain embodiments, n is 2. In certain other embodiments, n is 3. In yet other embodiments, n is 4, or 5, or 6. In certain embodiments, m is 2. In certain other embodiments, m is 3. In certain other embodiments, m is 4. In certain embodiments, n is 7. In certain other embodiments, n is 8. In yet other embodiments, n is 9, 10, 11 or 12.

In certain embodiments, W is NR1, and R1 and R3 together with the nitrogen atom to which they are attached, form a heterocycle selected from




in which RC is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, CH2CH2OH, or CH2CH2O(C1-C4)alkyl.

In certain embodiments, R5 is H, (C1-C6)alkyl, (C2-C6)alkenyl, phenyl, benzyl, CH2—S—(C1-C6)alkyl, CH2—O—(C1-C6)alkyl, (C2-C6)ORA, (C1-C6)-monoalkyl amine, (C1-C6)-dialkyl amine, or (C1-C6)-cyclic amine, in which said phenyl or benzyl is optionally substituted by one to three substitutents selected from (C1-C4)alkyl, (C1-C4)alkoxy, and halogen; and RA is H, (C1-C6)alkyl, phenyl, CH2-phenyl, (C1-C6)alkylOH, (CH2)pO(CH2)mOH, (CH2)pO(CH2)mO(CH2)mOH, (C1-C6)alkylO(C1-C4)alkyl, (CH2)pO(CH2)mO(C1-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(C1-C4)alkyl; p is an integer of 0, 1, 2, 3, 4, or 5; and m is an integer of 1, 2, 3, 4 or 5.
In certain embodiments, R5 is H. In certain other embodiments, R5 is methyl. In yet other embodiments, R5 is CH2—S—(C1-C6)alkyl, e.g., CH2—S—CH3. In yet other embodiments, R5 is CH2—O—(C1-C6)alkyl, e.g., CH2—O—CH2—CH3. In yet other embodiments, R5 is (C2-C6)alkenyl, e.g., CH2—CH═CH2. In yet other embodiments, R5 is benzyl. In yet other embodiments, R5 is (C2-C6)OH. In yet other embodiments, R5 is (C1-C6)-monoalkyl amine, e.g., CH2—NH-Me. In yet other embodiments, R5 is (C1-C6)-dialkyl amine, e.g., CH2—CH2—N(Et)2. In yet other embodiments, R5 is (C1-C6)-cyclic amine, e.g., CH2—CH2-morpholine.
In certain embodiments, each occurrence RA and RB is independently H, (C1-C6)alkyl, phenyl, CH2-phenyl, (C1-C6)alkylOH, (CH2)pO(CH2)mOH, or (CH2)pO(CH2)mO(CH2)mOH, (C1-C6)alkylO(C1-C4)alkyl, (CH2)pO(CH2)mO(C1-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(C1-C4)alkyl. In certain other embodiments, RA and RB, together with the nitrogen atom to which they are attached, form a heterocycle selected from




in which RC is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, CH2CH2OH, or CH2CH2O(C1-C4)alkyl.

In certain embodiments, wherein  represents a single bond. In certain other embodiments, wherein  represents a double bond.
In another aspect, the present invention provides a compound of Formulae (IIa)-(VIa):







or a pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each W is independently O, S, CH2, or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each p is independently an integer of 0, 1, 2, 3, 4, or 5; and
    each of m, n and q is independently an integer of 1, 2, 3, 4 or 5.


In another aspect, the present invention provides a compound of Formulae (IIa)-(VIa):







or a pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each W is independently O, S, CH2, or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each p is independently an integer of 0, 1, 2, 3, 4, or 5;
    each of m and n is independently an integer of 1, 2, 3, 4 or 5; and
    q is independently an integer of 6, 7, 8, 9, 10 or 11.


In another aspect, the present invention provides a compound of Formulae (IIb)-(VIb):







or a pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each p is independently an integer of 0, 1, 2, 3, 4, or 5; and
    each of m, n and q is independently an integer of 1, 2, 3, 4 or 5.


In another aspect, the present invention provides a compound of Formulae (IIb)-(VIb):







or a pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or R1 and R3 together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl;
    
    
    each R3 is independently:
    
        H;
        (C7-C12)alkyl, optionally substituted by one or more groups R4 which may be the same or different;
        (C7-C12)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA; or
        (C7-C12)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
    
    
    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R4 is independently halogen, hydroxy, (C3-C7)cycloalkyl, aryl (e.g., phenyl), O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)(C1-C6)alkyl, C(═O)ORA, C(═O)NRARB, —NRARB, —NRCCH2(CH2)pNRARB, NRC[CH2(CH2)pNRA]mCH2(CH2)nNRARB, O[CH2(CH2)pO]mCH2(CH2)nORA, OCH2(CH2)pNRARB, or O[CH2(CH2)pO]mCH2(CH2)nNRARB;
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each p is independently an integer of 0, 1, 2, 3, 4, or 5; and
    each of m and n is independently an integer of 1, 2, 3, 4 or 5.


In certain embodiments, R3 is (C7-C10)alkyl. In certain other embodiments, R3 is (C7-C8)alkyl. In yet other embodiments, R3 is (C7-C12) linear alkyl. In yet other embodiments, R3 is (C7-C10) linear alkyl. In yet other embodiments, R3 is (C7-C8) linear alkyl.
In certain embodiments, R4 is hydroxyl. In certain other embodiments, R4 is C(═O)ORA.
In certain embodiments, the compound of Formula I has the structure of Formulae (II) through (VI):







or a pharmaceutically acceptable salt thereof, wherein:

     represents a single bond or double bond;
    each W is independently O, S, CH2, or NR1;
    each R1 is independently hydrogen;
    
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
    
    
    each R3 is independently






    each R5 is independently:
    
        H;
        (C1-C6)alkyl, optionally substituted by one or more groups R6 which may be the same or different;
        (C2-C6)alkenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, aryl (e.g., phenyl), (CH2)pORA, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRC(CH2)mNRARB, (CH2)pNRC(CH2)mNRc(CH2)mNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
        (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
        phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB, (CH2)pC(═O)ORA;
    
    
    each occurrence of R6 is independently halogen, hydroxy, aryl (e.g., phenyl), S(C1-C6)alkyl, SRA, ORA, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(═O)ORA, C(═O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRC(CH2)mNRARB, or NRC(CH2)mNRC(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C1-C6)alkyl, (CH2)pORA, (CH2)pNRARB, (CH2)pC(═O)NRARB and (CH2)pC(═O)ORA;
    each occurrence of RA and RB is independently:
    
        hydrogen;
        (C1-C6)alkyl, optionally substituted by one or more groups RD which may be the same or different;
        (C2-C6)alkenyl or (C2-C6)alkynyl;
        (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl;
        phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, amino, alkylamino and dialkylamino;
        or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen;
        or RA and RB, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl;
    
    
    each occurrence of RC is independently hydrogen or (C1-C6)alkyl;
    each occurrence of RD is independently halogen, hydroxy, O(C1-C4)alkyl, C(═O)(C1-C4)alkyl, C(═O)O(C1-C4)alkyl;
    each p is independently an integer of 0, 1, 2, 3, 4, or 5; and
    each of m, n and q is independently an integer of 1, 2, 3, 4 or 5, or n is independently an integer of 6, 7, 8, 9, 10 or 11.


In certain embodiments, q is 1. In certain other embodiments, q is 2. In certain other embodiments, n is independently an integer of 6, 7, 8, 9, 10 or 11.
In certain embodiments, W is S. In certain other embodiments, W is O. In yet other embodiments, W is NH. In yet other embodiments, W is N—(C1-C4)alkyl.
In certain embodiments, R1 is hydrogen. In certain other embodiments, R1 is (C1-C6)alkyl. In certain embodiments, R3 is (C1-C6)alkyl. In certain other embodiments, R3 is NRCCH2(CH2)pNRARB.
In certain embodiments, R1 and R3 together with the nitrogen atom to which they are attached, form a heterocycle selected from




in which RC is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, CH2CH2OH, or CH2CH2O(C1-C4)alkyl.

In certain embodiments, R5 is H, (C1-C6)alkyl, (C2-C6)alkenyl, phenyl, benzyl, CH2—S—(C1-C6)alkyl, CH2—O—(C1-C6)alkyl, (C2-C6)ORA, (C1-C6)-monoalkyl amine, (C1-C6)-dialkyl amine, or (C1-C6)-cyclic amine, in which said phenyl or benzyl is optionally substituted by one to three substitutents selected from (C1-C4)alkyl, (C1-C4)alkoxy, and halogen; and RA is H, (C1-C6)alkyl, phenyl, CH2-phenyl, (C1-C6)alkylOH, (CH2)pO(CH2)mOH, (CH2)pO(CH2)mO(CH2)mOH, (C1-C6)alkylO(C1-C4)alkyl, (CH2)pO(CH2)mO(C1-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(C1-C4)alkyl; p is an integer of 0, 1, 2, 3, 4, or 5; and m is an integer of 1, 2, 3, 4 or 5.
In certain other embodiments, R5 is H, (C1-C4)alkyl, (C2-C4)alkenyl, phenyl, benzyl, CH2—S—(C1-C4)alkyl, CH2—O—(C1-C4)alkyl, (CH2)2OH, or (CH2)2O(C1-C4)alkyl. In certain embodiments, R5 is H. In certain other embodiments, R5 is methyl.
In certain embodiments, each occurrence RA and RB is independently H, (C1-C6)alkyl, phenyl, CH2-phenyl, (C1-C6)alkylOH, (CH2)pO(CH2)mOH, or (CH2)pO(CH2)mO(CH2)mOH, (C1-C6)alkylO(C1-C4)alkyl, (CH2)pO(CH2)mO(C1-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(C1-C4)alkyl. In certain other embodiments, each occurrence RA and RB is independently H or (C1-C6)alkyl. In yet other embodiments, RA and RB, together with the nitrogen atom to which they are attached, form a heterocycle selected from




in which RC is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, or CH2CH2OH and CH2CH2ORd.

In one aspect, the present invention provides a compound selected from the following:

























































































































or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a compound as described in the Examples.
In certain embodiments, the compounds are selected from:

    [(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxymethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxymethoxy)methyl-Sar]-3-cyclosporin sodium salt,
    [(R)-(Carboxymethoxy)methyl-Sar]-3-cyclosporin potassium salt,
    [(R)-(Methoxycarboxymethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxyethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxyethoxy)methyl-Sar]-3-cyclosporin sodium salt,
    [(R)-(Carboxyethoxy)methyl-Sar]-3-cyclosporin potassium salt,
    [(R)-(Methoxycarboxyethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxypropoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxypropoxy)methyl-Sar]-3-cyclosporin sodium salt,
    [(R)-(Carboxypropoxy)methyl-Sar]-3-cyclosporin potassium salt,
    [(R)-(Methoxycarboxypropoxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxypentyloxy)methyl-Sar]-3-cyclosporin,
    [(R)-(Carboxypentyloxy)methyl-Sar]-3-cyclosporin sodium salt,
    [(R)-(Carboxypentyloxy)methyl-Sar]-3-cyclosporin potassium salt,
    [(R)-(Methoxycarboxypentyloxy)methyl-Sar]-3-cyclosporin,
    [(R)-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]methyl-Sar]-3-cyclosporin,
    [(R)-[([HO-Gly-(D-Glu)6]carbamoyl)ethoxy]methyl-Sar]-3-cyclosporin,
    [(R)-[([HO-Gly-(D-Glu)6]carbamoyl)propoxy]methyl-Sar]-3-cyclosporin,
    [(R)-((2-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]ethoxy)methyl-Sar]-3-cyclosporin,
    [(R)-((3-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]propoxy)methyl-Sar]-3-cyclosporin,
    [(R)-((4-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]butoxy)methyl-Sar]-3-cyclosporin,
    [(R)-((5-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]pentyloxy)methyl-Sar]-3-cyclosporin,
    [(R)-((6-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]hexyloxy)methyl-Sar]-3-cyclosporin,
    [(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Methyl-N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Methyl-N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Ethyl-N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Ethyl-N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Methyl-N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Methyl-N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Ethyl-N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Ethyl-N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Ethyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Ethyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Methyl-N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Methyl-N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Ethyl-N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Ethyl-N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Methyl-N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Methyl-N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Ethyl-N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Ethyl-N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Methyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(R)-(4-(N-Methyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Ethyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Ethyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(4-Ethyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(4-Ethyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Ethyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Ethyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Propyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Propyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Propyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Propyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Isopropyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Isopropyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Isopropyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Isopropyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Isobutyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Isobutyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Isobutyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Isobutyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Neopentyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(4-Neopentyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Neopentyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(4-Neopentyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ-Methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[(γ-Methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(2-(N,N-Diethylamino)ethoxy)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(2-(N,N-Diethylamino)ethoxy)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Hydroxyl-3,3-dimethylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-Hydroxyl-3,3-dimethylpropylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Hydroxyl-4,4-dimethylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-Hydroxyl-4,4-dimethylbutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Hydroxylpentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Methoxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Hydroxyl-5,5-dimethylpentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Hydroxylpentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Methoxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Hydroxyl-5,5-dimethylpentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin, and
    [(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
    [(S)-(5-Carboxyheptylthio)methyl-Sar]-3-cyclosporin
    [(S)-(5-Carboxyheptylthio)methyl-Sar]-3-cyclosporin-potassium salt
    [(S)-(5-(Ethoxycarbonyl)heptylthio)methyl-Sar]-3-cyclosporin
    [(S)-((7,7′-Dicarboxy)heptylthio)methyl-Sar]-3-cyclosporin
    [(S)-((7,7′-Dicarboxy)heptylthio)methyl-Sar]-3-cyclosporin-dipotassium salt
    [(S)-((7,7′-Dicarboxy)heptylthio)methyl-Sar]-3-cyclosporin-disodium salt
    [(S)-(7,7′-Diethoxycarbonyl)heptylthio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(imidazol-1-yl)hexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-(imidazo-1-yl)hexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(4-ethylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-(4-isopropylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(imidazol-1-yl)heptyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(imidazo-1-yl)heptyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-cyclosporin
    [(R)-(5-Carboxyheptyloxy)methyl-Sar]-3-cyclosporin
    [(R)-(5-Carboxyheptyloxy)methyl-Sar]-3-cyclosporin-potassium salt
    [(R)-((7,7′-Dicarboxy)heptyloxy)methyl-Sar]-3-cyclosporin
    [(R)-((7,7′-Dicarboxy)heptyloxy)methyl-Sar]-3-cyclosporin-dipotassium salt
    [(R)-(7,7′-Diethoxycarbonyl)heptyloxy)methyl-Sar]-3-cyclosporin
    [(R)-(((S)-4-Hydroxy-7-(imidazol-1-yl)heptyl)oxy)methyl-Sar]-3-cyclosporin
    [(R)-(((R)-4-Hydroxy-7-(imidazo-1-yl)heptyl)oxy)methyl-Sar]-3-cyclosporin
    [(R)-(((S)-4-Hydroxy-7-morpholinoheptyl)oxy)methyl-Sar]-3-cyclosporin
    [(R)-(((R)-4-Hydroxy-7-morpholinoheptyl)oxy)methyl-Sar]-3-cyclosporin
    [(R)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptylcyclos)oxy)methyl-Sar]-3-cyclosporin
    [(R)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)oxy)methyl-Sar]-3-cyclosporin
    [(S)-(7,7′-Di(carboxy)heptylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(7,7′-Di(carboxy)heptylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin-dipotassium salt
    [(S)-(7,7′-Di(ethoxycarbonyl)heptylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(imidazol-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(imidazo-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(imidazol-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-(imidazo-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(4-ethylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-(4-isopropylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(R)-(7,7′-Di(carboxy)heptyloxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(R)-(7,7′-Di(carboxy)heptyloxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin-dipotassium salt
    [(R)-(7,7′-Di(ethoxycarbonyl)heptyloxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(imidazol-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(imidazo-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-morpholinoheptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(imidazol-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-(imidazo-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((S)-3-Hydroxymethyl-6-morpholinohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin
    [(S)-(((R)-3-Hydroxymethyl-6-(4-ethylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin, and
    [(S)-(((S)-3-Hydroxymethyl-6-(4-isopropylpiperazin-1-yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin, or a pharmaceutically acceptable salt thereof.


In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound described herein and a pharmaceutically-acceptable carrier or diluent.
In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein. In certain embodiments, the viral infection is HIV infection. In certain other embodiments, the viral infection is HBV infection. In yet other embodiments, the viral infection is HCV infection. In yet other embodiments, the viral infection is influenza A virus infection, severe acute respiratory syndrome coronavirus infection or vaccinia virus infection.
In another aspect, the present invention provides a method for treating or preventing hepatitis C virus infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein.
In yet another aspect, the present invention provides a method for inhibiting a cyclophilin in a subject in need thereof, which comprises administrating to said subject an effective cyclophilin-inhibiting amount of at least one compound as described herein.
In yet another aspect, the present invention provides a method for treating or preventing diseases that are mediated by cyclophilins in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's Diseases, and ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kidney.
In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from cardiovascular diseases, vascular stenosis, atherosclerosis, abdominal aortic aneurysms, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases.
In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from cancer, obesity, diabetes, muscular dystrophy, and hair loss.
In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from allergic conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, Behcet's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, corneal transplant rejection, corneal sensitivity impaired due to surgery on the cornea or other surface of the eye, meibomian gland disease, ptyregia, ocular symptoms of graft versus host disease, ocular allergy, ocular cicatricial pemphigoid, Steven Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, ocular rosacea, and Pinguecula.
Methods of Preparation
In certain embodiments, the compound of formulae (I) and (II) can be prepared by treating cyclosporin A or an analog thereof with a base (e.g., LDA) to form a sarcosine enolate at 3-position, and then CO2 gas is introduced to yield carboxylic acid-3-cyclosporin, after formation of its corresponding methyl ester and reduction of the methyl ester side chain to alcohol, its mesylate, tosylate or chloride can be formed by treatment with MsCl or TsCl in dichloromethane solution, and they can be converted to the methylene on the sarcosine by treatment with a base (e.g., NaH), when sulfur nuclectrophile is used for 1,4-addition reaction on the methylene group, the methylene sulfur side chain with S-conformation can be formed on the sarcosine of position 3 as novel cyclosporine derivatives. For example:










[α-Methylene-Sar]-3-cyclosporin can also be prepared using a method analogous to the procedure described in Reference Example 2 or WO2012/051194A1 (which is incorporated herein by reference).
In certain embodiments, the above resulting methylene-3-cyclosporin can be converted to its methylene amine side chain to form novel cyclosporine derivatives. For example:




Therefore, the following derivatives can be prepared by this procedure.

























In certain embodiments, the above resulting alcohol can be converted to its methylene oxygen ether side chain to form novel cyclosporine derivatives too. For example:




In Schemes 1-4 above, the symbols have the same meaning as defined in the claims and throughout the specification, unless otherwise noted.
In certain other embodiments, the compound of formula (IIa) or (IIIa) can be obtained according to the procedures described herein.
Pharmaceutical Compositions
This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically-acceptable salt or solvate thereof, and a pharmaceutically-acceptable carrier.
The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically-acceptable salts. The term “pharmaceutically-acceptable salt”, in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).
The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets, may be, made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying butortions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples are embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if apbutriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl-.beta.-cyclodextrin, may be used to solubilize compounds.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active pharmaceutical agents of the invention.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be apbutriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or butellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary butellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and butane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the buter medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polybutylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anti-HCV agent), or they may achieve different effects (e.g., control of any adverse effects).
The compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds may be used to treat arthritic conditions in mammals (i.e., humans, livestock, and domestic animals), birds, lizards, and any other organism, which can tolerate the compounds.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
EQUIVALENTS
The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
EXAMPLES
Example 1
[α-Methoxycarbonyl-Sar]-3-cyclosporin




[α-Carboxy-sar]-3-cyclosporin (5.00 g, 4.01 mmol) was dissolved in N,N-dimethylformamide (30 ml). Iodomethane (2.85 g, 20.10 mmol) and potassium carbonate (1.38 g, 10.00 mmol) were added. The mixture was stirred at room temperature for 2 hours. Then ethyl acetate (60 ml) and water (60 ml) were added and the mixture was separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5.32 g of crude product, which was directly used for the next step without purification (yield:  ̃100%) [Molecular Formula: C64H113N11O14; Exact Mass: 1259.85; MS (m/z): 1260.7 (M+1)+, 1282.7 (M+Na)+; TLC Rf: 0.55 (dichloromethane/methanol=9/1)].
Example 2
[(R)-α-Hydroxymethyl-Sar]-3-cyclosporin




[α-Methoxycarbonyl-Sar]-3-cyclosporin (2.00 g, 1.59 mmol) was dissolved in tetrahydrofuran (30 ml). Cesium chloride (1.33 g, 7.90 mmol) and sodium borohydride (0.60 g, 15.89 mmol) were added in portions. Then methanol (30 ml) was added dropwise to the mixture over 2 hours. After addition, the mixture was stirred at room temperature overnight. Most of solvent was then evaporated under reduced pressure. Ethyl acetate (50 ml) and water (50 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1.99 g of crude product, which was purified by on silica gel column with dichloromethane/methanol (from 100:0 to 95:5) to give the 1.50 g of pure product (yield: 76%) [Molecular Formula: C63H113N11O13; Exact Mass: 1231.85; MS (m/z): 1232.7 (M+1)+, 1254.7 (M+Na)+].
Example 3
[α-Methylmethanesulfonate-Sar]-3-cyclosporin




To a solution of [α-hydroxymethyl-Sar]-3-cyclosporin (30 mg, 0.024 mmol) in dichloromethane (2 ml) at 0° C. were added triethylamine (52.8 μl, 0.38 mmol), and methanesulfonyl chloride (23 mg, 0.20 mmol). The mixture was stirred at room temperature for two hours. Then reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 33 mg of crude product, which was directly used in next step reaction without further purification [Molecular Formula: C64H115N11O15S; Exact Mass: 1309.83; MS (m/z): 1310.7 (M+1)+].
Example 4
[α-Chloromethyl-Sar]-3-cyclosporin




To a solution of [α-hydroxymethyl-Sar]-3-cyclosporin (30 mg, 0.024 mmol) in dichloromethane (2 ml) at 0° C. were added triethylamine (52.8 μl, 0.384 mmol, 16 equivalents) and methanesulfonyl chloride (23 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 30 mg of crude product, which was directly used in next step reaction without further purification [Molecular Formula: C63H112ClN11O12; Exact Mass: 1249.82; MS (m/z): 1250.7 (M+1)+, 1272.9 (M+Na)+].
Example 5
[α-Methylene-Sar]-3-cyclosporin*




To a solution of either [α-methanesulfonatemethyl-Sar]-3-cyclosporin (33 mg, 0.025 mmol) or [α-chloromethyl-Sar]-3-cyclosporin (30 mg, 0.025 mmol) in tetrahydrofuran (3 ml) was added sodium hydride (15.3 mg, 60% in oil, 0.38 mmol, 10 equivalents) at 0° C. The mixture was stirred at 0° C. for one hour and then warmed up to room temperature for 30 minutes. After removal of solvent, the residue was dissolved in dichloromethane (20 ml). The dichloromethane layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethylene/methanol (20/1) to give 16 mg of product (yield: 54%) [Molecular Formula: C63H111N11O12; Exact Mass: 1213.84; MS (m/z): 1214.7 (M+1)+, 1236.7 (M+Na)+; TLC Rf: 0.55 (ethyl acetate/methanol=20/1); HPLC RT: 7.0 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
[α-Methylene-Sar]-3-cyclosporin can also be prepared by a method analogous to the procedure described in WO2012/051194A1 (which is incorporated herein by reference).
Example 6
[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-cyclosporin (Isomer B) and [(R)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-cyclosporin (Isomer A)




To a solution of [α-methylene-Sar]-3-cyclosporine (0.60 g, 0.50 mmol) and 2-(dimethylamino)ethanethiol (0.63 g, 6.00 mmol) in methanol (20 ml) was added triethylamine (0.82 ml, 6.0 mmol). The reaction mixture was stirred overnight at room temperature. After removal of solvent, the residue was subjected to chromatography using dichloromethane/methanol as eluent to give 0.35 g of (R)-2-(N,N-dimethylamino)ethylthiomethyl-Sar]-3-cyclosporin (isomer A) and 0.20 g of [(S)-2-(N,N-dimethylamino)ethylthiomethyl-Sar]-3-cyclosporin (isomer B) [Molecular Formula: C67H122N12O12S; Exact Mass: 1218.9; MS (m/z): 1319.80 (M+1)+; TLC Rf: 0.20 (ethyl acetate/methanol=5/1); HPLC RT: 12.55 min (isomer A) and 13.22 min (isomer B) (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 7
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-cyclosporin (Isomer B) and [(R)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-cyclosporin (Isomer A)




To a solution of [α-methylene-Sar]-3-cyclosporin (0.31 g, 0.25 mmol) and 2-diethylaminoethanethiol (0.40 g, 3.00 mmol) in methanol (10 ml) was added triethylamine (0.41 ml, 3.00 mmol, 12 equivalents). The reaction mixture was stirred overnight at room temperature. After removal of solvent, the residue was subjected to chromatography using dichloromethane/methanol as eluent to yield 0.20 g of [(R)-2-(N,N-Diethylamino)ethylthiomethyl-Sar]-3-cyclosporin (isomer A) and 0.08 g of [(S)-2-(N,N-Diethylamino)ethylthiomethyl-Sar]-3-cyclosporin (isomer B) [Molecular Formula: C69H126N12O12S; Exact Mass: 1346.93; MS (m/z): 1347.80 (M+1)+; TLC Rf: 0.23 (ethyl acetate/methanol=5/1); HPLC RT: 13.37 min (isomer A) and 13.91 min (isomer B) (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 8
[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.36 g, 0.29 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.20 g, 30 mmol) in water (2 ml), 2-bromo-N,N-diethylethylamine hydrobromide (3.80 g, 14.56 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). The reaction mixture was stirred at 30° C. for 20 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 210 mg of product [Molecular Formula: C69H126N12O13; Exact Mass: 1330.96; MS (m/z): 1331.71 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=95/5); HPLC RT: 14.12 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 9
[(R)-(tert-Butoxycarbonylmethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.50 g, 0.41 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.00 g, 25.00 mmol) in water (1 ml), t-butyl bromoacetate (3.20 g, 16.41 mmol) and tetra-n-butylammonium bromide (0.40 g, 1.24 mmol). The mixture was stirred at room temperature for 10 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone=2/1) to give 0.41 g product [Molecular Formula: C69H123N11O15; Exact Mass: 1345.92; MS (m/z): 1346.61 (M+1)+; TLC Rf: 0.60 (dichloromethane/methanol=95/5); HPLC RT: 18.29 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 10
[(R)-(Ethoxycarbonylmethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.35 g, 0.28 mmol) in benzene (15 ml) were added a solution of sodium hydroxide (0.60 g, 15.00 mmol) in water (1 ml), ethyl bromoacetate (1.60 g, 9.58 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). The mixture was stirred at room temperature for 10 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (15 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone=2/1) to give 0.31 g of product [Molecular Formula: C67H119N11O15; Exact Mass: 1317.89; MS (m/z): 1318.46 (M+1)+; TLC Rf: 0.55 (dichloromethane/methanol=95/5); HPLC RT: 17.40 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 11
[(R)-(Carboxymethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-((tert-butoxycarbonyl)methoxy)methyl-Sar]-3-cyclosporin (0.18 g, 0.13 mmol) in dichloromethane (5 ml) were added trifluoroacetic acid (1 ml) and triethylsilane (10 drops). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. Then dichloromethane (10 ml) and water (10 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by C-18 chromatography (acetonitrile/water) to give 75 mg of product [Molecular Formula: C65H115N11O15; Exact Mass: 1289.86; MS (m/z): 1290.56 (M+1)+; HPLC RT: 11.03 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 12
[(R)-(Carboxymethoxy)methyl-Sar]-3-cyclosporin-sodium salt




To a solution of [(R)-(carboxymethoxy)methyl-Sar]-3-cyclosporin (30 mg, 0.02 mmol) in methanol (1 ml) was added a solution of sodium hydroxide (1.00 mg, 0.02 mmol) in water (0.5 ml). The mixture was stirred at room temperature 1 hour and dried in high vacuum to give 28 mg of product [Molecular Formula: C65H114N11NaO15; Exact Mass: 1311.84; MS (m/z): 1290.56 (M+1−Na)+; HPLC RT: 10.98 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 13
[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-(ethoxycarbonylmethoxy)methyl-Sar]-3-cyclosporin (0.25 g, 0.19 mmol) in methanol (30 ml) were added lithium chloride (0.33 g, 7.85 mmol) and sodium borohydride (0.60 g, 15.89 mmol) in portions. After addition, the mixture was stirred at room temperature overnight. Most of solvent was then evaporated under reduced pressure. Ethyl acetate (50 ml) and water (50 ml) were added. The ethyl acetate layer was separated and washed with brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel column with (dichloromethane/methanol=95/5) to give the product [Molecular formula: C65H117N11O14; Exact Mass: 1275.88; MS (m/z): 1276.55 (M+1)+; TLC Rf: 0.39 (dichloromethane/methanol=9/1); HPLC RT: 15.31 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 14
[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (1.03 g, 0.84 mmol) in benzene (50 ml) were added a solution of sodium hydroxide (1.34 g, 33.47 mmol) in water (1.34 ml), tetramethylammonium hydroxide pentahydrate (3.04 g, 16.73 mmol) and 2-dimethylaminoethyl chloride hydrochloride (2.41 g, 16.73 mmol). The mixture was stirred at room temperature for 5 days. Sodium bicarbonate saturated solution (100 ml) was added and the mixture was separated. Then the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 303 mg of product was obtained [Molecular Formula: C67H122N12O13; Exact Mass: 1302.93; MS (m/z): 1303.70 (M+1)+, 1325.85 (M+Na)+; TLC Rf: 0.36 (dichloromethane/methanol=9/1); HPLC RT: 18.19 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 15
[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.27 g, 0.22 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (0.70 g, 17.55 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (0.80 g, 4.39 mmol) and 2-(4-morpholinyl)ethyl chloride hydrochloride (0.82 g, 4.39 mmol). The mixture was stirred at 30 to 40° C. for a week. Sodium bicarbonate saturated solution (30 ml) was added and then the mixture was separated. The aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 56 mg of product was obtained [Molecular Formula: C69H124N12O14; Exact Mass: 1344.94; MS (m/z): LCMS: 1345.72 (M+1)+, 1367.83 (M+Na)+; TLC Rf: 0.50 (dichloromethane/methanol=9/1); HPLC RT: 16.64 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 16
[(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.320 g, 0.26 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (0.83 g, 20.80 mmol) in water (0.85 ml), tetramethylammonium hydroxide pentahydrate (0.95 g, 5.20 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (0.88 g, 5.20 mmol). The mixture was stirred at room temperature for a weekend. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 103 mg of product was obtained [Molecular Formula: C69H124N12O13; Exact Mass: 1328.94; MS (m/z): 1329.75 (M+1)+, 1351.82 (M+Na)+; TLC Rf: 0.37 (dichloromethane/methanol=9/1); HPLC RT: 18.94 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 17
[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (0.28 g, 0.22 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (0.36 g, 9.07 mmol) in water (0.36 ml), tetramethylammonium hydroxide pentahydrate (0.82 mg, 4.53 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.83 g, 4.53 mmol). The mixture was stirred at 30 to 40° C. for 20 hours. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. Then the aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 121 mg of product was obtained [Molecular Formula: C70H126N12O13; Exact Mass: 1342.96; MS (m/z): 1343.76 (M+1)+, 1365.83 (M+Na)+; TLC Rf: 0.44 (dichloromethane/methanol=9/1); HPLC RT: 19.26 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 18
[(R)-(3,3-Dimethoxypropoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-hydroxymethyl-Sar]-3-cyclosporin (0.50 g, 0.41 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.00 g, 25.00 mmol) in water (1 ml), 3-bromopropionaldehyde dimethyl acetal (1.80 g, 10.00 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). After stirred at room temperature for 10 hours, the mixture was diluted with ice water and the mixture was separated. The aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 0.48 g of crude product, which was used for next step [Molecular Formula: C68H123N11O15; Exact Mass: 1333.92; MS (m/z): 1334.50 (M+1)+].
Example 19
[(R)-(2-Formylethoxy)methyl-Sar]-3-cyclosporin




To a solution of crude [(R)-(3,3-dimethoxypropoxy)methyl-Sar]-3-cyclosporin (0.48 g, 0.36 mmol) in dichloromethane (30 ml) were added trifluoroacetic acid (5 ml) and water (4 ml) at 0° C. Then the mixture was allowed to warm to room temperature and stirred for 3 hours. After the mixture was separated, the dichloromethane layer was washed with saturated sodium bicarbonate solution (20 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone=2/1) to give 0.31 g of product [Molecular Formula: C66H117N11O14; Exact Mass: 1287.88; MS (m/z): 1288.63 (M+1)+].
Example 20
[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-(2-formylethoxy)methyl-Sar]-3-cyclosporin (0.13 g, 0.10 mmol) in chloroform (5 ml) were added dimethylamine hydrochloride (0.10 g, 1.22 mmol) and acetic acid (5 drops). After the mixture was stirred at room temperature for 5 minutes, tetramethylammonium triacetoxyborohydride (65 mg, 0.25 mmol) was added in portions and stirring was continued for one hour. Then dichloromethane (10 ml) and saturated sodium bicarbonate solution (10 ml) were added and separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 89 mg of product [Molecular Formula: C68H124N12O13; Exact Mass: 1316.94; MS (m/z): 1317.64 (M+1)+; TLC Rf: 0.39 (dichloromethane/methanol=95/5); HPLC RT: 13.92 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 21
[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-(2-formylethoxy)methyl-Sar]-3-cyclosporin (100 mg, 0.08 mmol) in chloroform (4 ml) were added diethylamine (100 mg, 1.37 mmol) and acetic acid (4 drops). After the mixture was stirred at room temperature for 5 minutes, tetramethylammonium triacetoxyborohydride (50 mg, 0.19 mmol) was added in portions and stirring was continued for 1 hour. Then dichloromethane (10 ml) and saturated sodium bicarbonate solution (10 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 56 mg of product [Molecular Formula: C70H128N12O13; Exact Mass: 1344.97; MS (m/z): 1345.71 (M+1)+; TLC Rf: 0.40 (dichloromethane/methanol=95/5); HPLC RT: 14.59 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 22
[(R)-(3-(N-Morphlino)propoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-(2-formylethoxy)methyl-Sar]-3-cyclosporin (300 mg, 0.23 mmol) in dichloromethane (15 ml) were added morpholine (101 mg, 1.16 mmol) and tetramethylammonium triacetoxyborohydride (306 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for two hours. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 124 mg of product was obtained [Molecular Formula: C70H126N12O14; Exact Mass: 1358.95; MS (m/z): 1359.71 (M+1)+, 1381.79 (M+Na)+; TLC Rf: 0.40 (dichloromethane/methanol=9/1); HPLC RT: 14.2 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 23
[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-cyclosporin (315 mg, 0.24 mmol) in dichloromethane (15 ml) were added pyrrolidine (87 mg, 1.22 mmol) and tetramethylammonium triacetoxyborohydride (322 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for two hours. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 22 mg of product was obtained [Molecular Formula: C70H126N12O13; Exact Mass: 1342.96; MS (m/z): 1343.75 (M+1)+, 1365.82 (M+Na)+; TLC Rf: 0.33 (dichloromethane/methanol=9/1); HPLC RT: 14.3 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 24
[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-cyclosporin




To a solution of [(R)-(2-formylethoxy)methyl-Sar]-3-cyclosporine (350 mg, 0.27 mmol) in dichloromethane (20 ml) were added piperidine (115 mg, 1.34 mmol) and tetramethylammonium triacetoxyborohydride (352 mg, 1.34 mmol). The reaction mixture was stirred overnight at room temperature. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 35 mg of product was obtained [Molecular Formula: C71H128N12O13; Exact Mass: 1356.97; MS (m/z): 1357.76 (M+1)+, 1379.83 (M+Na)+; TLC Rf: 0.36 (dichloromethane/methanol=9/1); HPLC RT: 14.4 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 25
[α-Carboxy-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of LDA (2.0 M in tetrahydrofuran, 23 ml, 46 mmol) in tetrahydrofuran (80 ml) at −78° C. under nitrogen, [(γ-hydroxy)-N-MeLeu]-4-cyclosporin (4.40 g, 3.61 mmol) in tetrahydrofuran (15 ml) was added over 3 min. After the mixture was stirred at −78° C. for 3 hours, carbon dioxide gas was bubbled into the reaction mixture for 1 hour. Then the mixture was allowed to warm to room temperature slowly and kept stirring for 3 hours. Most of tetrahydrofuran was evaporated. Dichloromethane (100 ml) and water (50 ml) were added. The PH of the mixture was adjusted to around 5 by adding aqueous citric acid solution. The mixture was separated and the organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3.20 g of crude product, which was used for next step without purification [Molecular Formula: C63H111N11O15; Exact Mass: 1261.83; MS (m/z): 1262.49 (M+1)+].
[(γ-Hydroxy)-N-MeLeu]-4-cyclosporin was prepared by Sebekia benihana biotransformation according to a method described by Kuhnt M. et al., 1996, Microbial Biotransformation Products of Cyclosporin A, J. Antibiotics, 49 (8), 781.
Example 26
[α-Methoxycarbonyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a mixture of [α-carboxy-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (3.20 g 2.53 mmol) and potassium carbonate (1.30 g, 9.40 mmol) in N,N-dimethylformamide (20 ml) was added iodomethane (1.80 g, 12.70 mmol). The mixture was stirred overnight at room temperature. Dichloromethane (80 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and evaporated under reduced pressure to give crude 3.00 g of product [Molecular Formula: C64H113N11O15; Exact Mass: 1275.84; MS (m/z): 1276.75 (M+1)+].
Example 27
[(R)-α-Hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a suspension of [α-methoxycarbonyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (3.00 g, 2.35 mmol) and lithium chloride (1.50 g, 35.30 mmol) in methanol (100 ml) was added sodium borohydride (2.50 g, 66.10 mmol) in portions. The mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 1.30 g of product [Molecular Formula: C63H113N11O14; Exact Mass: 1247.85; MS (m/z): 1248.48 (M+1)+; 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.68 (d, J=5.4 Hz, 3H), 0.80-1.00 (m, 30H), 1.07 (d, J=6.0 Hz, 3H), 1.16-1.29 (m, 10H), 1.32 (d, J=7.2 Hz, 3H), 1.39-1.46 (m, 2H), 1.59-1.63 (m, 6H), 1.68-1.83 (m, 7H), 2.02-2.11 (m, 4H), 2.31-2.33 (m, 1H), 2.37-2.42 (m, 2H), 2.67 (s, 6H), 3.09 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.22 (s, 3H), 3.47 (s, 3H), 3.72-3.75 (m, 1H), 3.82 (br, 1H), 3.97-3.99 (m, 1H), 4.07-4.10 (m, 1H), 4.50-4.52 (m, 1H), 4.65-4.67 (t, J=8.4 Hz, 1H), 4.79-4.81 (m, 1H), 4.90-4.95 (m, 2H), 5.00-5.05 (m, 2H), 5.09 (d, J=10.8 Hz, 1H), 5.30-5.35 (m, 2H), 5.46 (d, J=6.0 Hz, 1H), 5.52-5.53 (m, 1H), 5.66-5.68 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.87-7.89 (d, J=9.6 Hz, 1H)].
Example 28
[α-Methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin
Method 1




To a solution of [α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in dichloromethane (10 mL) at room temperature were added triethylamine (0.33 mL, d 0.726, 2.40 mmol) and triethylamine hydrochloride (95.6 mg, 1.00 mmol), followed by adding p-toluenesulfonyl chloride (0.23 g, 1.20 mmol) under stirring. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with brine, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The reaction mixture of [α-chloromethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C63H112ClN11O13; Exact Mass: 1265.81; MS (m/z): 1266.32 (M+1)+, 1288.43 (M+Na)+] and [α-p-toluenesulfonylmethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C70H119N11O16S; Exact Mass: 1401.856; MS (m/z): 1402.34 (M+1)+, 1424.62 (M+Na)+] was directly used in next step reaction without further purification. To a solution of the above mixture in tetrahydrofuran (20 ml) was added sodium hydride (320 mg, 60% in oil, 8 mmol) at 0° C. The mixture was stirred at 0° C. for one hour and then warmed up to room temperature for 30 minutes. The reaction was quenched with a saturated ammonia chloride solution. After removing tetrahydrofuran, the crude product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (20/1) to give 45 mg of product (yield: 18%) [Molecular formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.6 (M+1)+, 1252.82 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol=10/1); HPLC RT: 15.38 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm); 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.72 (d, J=5.4 Hz, 3H), 0.84-1.00 (m, 30H), 1.17-1.26 (m, 15H), 1.34 (d, J=6.0 Hz, 3H), 1.44-1.47 (m, 2H), 1.59-1.62 (m, 6H), 1.69-1.76 (m, 4H), 1.94-1.99 (m, 1H), 2.09-2.13 (m, 3H), 2.34-2.37 (m, 3H), 2.65 (s, 3H), 2.67 (s, 3H), 3.09 (s, 3H)), 3.10 (s, 3H), 3.19 (s, 3H), 3.44 (s, 3H), 3.46 (s, 3H), 3.80 (m, 1H), 3.91 (m, 1H), 4.47-4.50 (m, 1H), 4.68-4.71 (t, J=9.0 Hz, 1H), 4.78-4.81 (m, 1H), 4.98-5.02 (m, 2H), 5.06-5.11 (m, 3H), 5.24 (s, 1H), 5.32 (m, 2H), 5.41-5.43 (m, 2H), 5.64-5.66 (m, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H)].
Method 2




[(R)-α-Hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (crude, 2.00 g), carbon tetrabromide (2.66 g, 8.02 mmol) and triphenylphosphine (2.11 g, 8.02 mmol) were dissolved in dichloromethane (30 ml). The mixture was stirred under nitrogen at room temperature for two hours. Then the mixture was added into a suspension of sodium hydride (60% dispersion in mineral oil) (0.77 g, 19.25 mmol) in tetrahydrofuran (30 ml) under nitrogen at 0° C. The mixture was stirred at 0° C. for one hour. Most of solvents then were evaporated under reduced pressure. The residue was treated with water (10 ml) slowly at 0° C. Ethyl acetate (30 ml) and water (30 ml) were added and the mixture was separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone from 90/10 to 70/30) to give 0.68 g product of [α-methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.50 (M+1)+, 1252.68 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol=10/1); HPLC RT: 15.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Method 3




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in methylene chloride (10 mL) was added dropwise 1-chloro-N,N,2-trimethyl-1-propenylamine (131 μl, d 1.01, 1.0 mmol) at 0° C. under nitrogen atmosphere. After stirred for 30 minutes at 0° C., the mixture was allowed to warm to room temperature and stirred for another hour. The reaction mixture was washed with sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product containing [α-chloromethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C63H112ClN11O13; Exact Mass: 1265.81; MS (m/z): 1266.32 (M+1)+, 1288.43 (M+Na)] was used in next step reaction without further purification. To a solution of the above crude product in tetrahydrofuran (20 ml) was added sodium hydride (320 mg, 60% in oil, 8 mmol) at 0° C. under stirring. The mixture was stirred at 0° C. for one hour and then warmed up to room temperature for another 30 minutes. The reaction was then quenched with a saturated ammonia chloride solution. After removing tetrahydrofuran, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (20/1) to give 33 mg of product (yield: 13%) [Molecular formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.45 (M+1)+, 1252.65 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol=10/1); HPLC RT: 15.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Method 4




n-Buli (2.2 M, 49.30 ml, 108.46 mmol) was added into a solution of diisopropylamine (15.39 ml, 108.46 mmol) in tetrahydrofuran (150 ml) at −78° C. under nitrogen. After the reaction mixture was stirred for an hour, a solution of [(γ-hydroxy)-NMeLeu]-4-cyclosporin (12.00 g, 9.86 mmol) in tetrahydrofuran (30 ml) was added over 10 min. The stirring was continued at −78° C. for two hours. Carbon dioxide gas was bubbled through the reaction mixture for two hour and the mixture was stirred at −78° C. for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature slowly with bubbling out of unreacted carbon dioxide. The mixture was cooled to about 0-5° C. by ice bath and chloromethyl chloroformate (13.98 g, 108.46 mmol) was added. The mixture was allowed to warm to room temperature and stirred for overnight. Water (30 ml) was added to quench the reaction. Most of solvent was then evaporated under reduced pressure. Ethyl acetate (100 ml) and water (80 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with hexane/acetone (from 90:10 to 70:30) as eluent to give 4.74 g of pure product of [α-Methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin* [Molecular Formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.39 (M+1)+, 152.59 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol=10/1); HPLC RT: 15.38 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Synthesis of [α-Methylene-Sar]-3-cyclosporin can also be prepared using a method analogous to that described in WO2012/051194A1.
Example 29
[(S)-(Methoxycarbonylmethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and methylmercaptoacetate (0.24 g, 2.00 mmol) were dissolved in acetonitrile (15 ml), followed by adding 20 equivalents of potassium carbonate (0.55 g, 4.0 mmol). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was dissolved in dichloromethane (20 ml). The dichloromethane solution was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subject to the flash chromatography using ethyl acetate/methanol as eluent to give product. [Molecular formula: C66H117N11O15S; Exact Mass: 1335.84; MS (m/z): 1336.50 (M+1)+, 1358.80 (M+Na)+; TLC Rf: 0.30 (ethyl acetate/methanol=20/1); HPLC RT: 14.33 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 30
[(S)-(2-Aminoethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.86 g, 0.70 mmol) and 2-aminoethanethiol hydrochloride (0.80 g, 7.00 mmol) were dissolved in methanol (80 ml), followed by adding 20 equivalents of lithium hydroxide (0.17 g, 7.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was subjected to the flash chromatography using dichloromethane/methanol as eluent to give 0.60 g of product [Molecular Formula: C65H118N12O13S; Exact Mass: 1306.87; MS (m/z): 1307.56 (M+1)+, 1329.73 (M+Na)+, TLC Rf: 0.025 (dichloromethane/methanol=5/1); HPLC RT: 10.97 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 31
[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (Isomer B) and [(R)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (Isomer A)




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.62 g, 0.50 mmol) and 2-(dimethylamino)ethanethiol (0.49 g, 6.00 mmol) were dissolved in methanol (30 ml) followed by adding triethylamine (0.82 ml, 6.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was subjected to chromatography using dichloromethane/methanol as eluent to yield 0.41 g of [(R)-(2-(N,N-dimethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (isomer A) and 0.18 g of [(S)-(2-(N,N-dimethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (isomer B) [Molecular Formula: C67H122N12O13S; Exact Mass: 1334.9; MS (m/z): 1335.7 (M+1)+; TLC Rf: 0.05 (ethyl acetate/methanol=5/1); HPLC RT: 10.88 min (isomer A) and 11.30 min (isomer B) (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 32
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (Isomer B) and [(R)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (Isomer A)




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.31 g, 0.25 mmol) and 2-diethylaminoethanethiol (0.40 g, 3.00 mmol) were dissolved in methanol (30 ml), followed by adding triethylamine (0.41 ml, 3.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was subjected to chromatography using dichloromethane/methanol as eluent to yield 0.15 g of [(R)-(2-(N,N-diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy-N-MeLeu]-4-cyclosporin (isomer A) and 0.10 g of [(S)-(2-(N,N-diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy-N-MeLeu]-4-cyclosporin (isomer B) [Molecular Formula: C69H126N12O13S; Exact Mass: 1362.93; MS (m/z): 1363.75 (M+1)+; TLC Rf: 0.1 (ethyl acetate/methanol=5/1); HPLC RT: 11.64 min (isomer A) and 11.85 min (isomer B) (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 33
[(S)-(2-(N-Isopropylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(Amino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.31 g, 0.25 mmol) and acetone (0.40 ml, 5.44 mmol) were dissolved in chloroform (30 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (164 mg, 0.63 mmol) in portions and a few drops of acetic acid. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using methylene/methanol as eluent to give 0.25 g of pure product [Molecular Formula: C68H124N12O13S; Exact Mass: 1348.91; MS (m/z): 1349.59 (M+1)+; TLC Rf: 0.1 (ethyl acetate/methanol=5/1); HPLC RT: 11.97 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 34
[(S)-(2-(N-Isopropyl-N-methylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-Isopropylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (49 mg, 0.034 mmol) and formaldehyde (100 μl, 37% in water) were mixed with chloroform (10 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (22 mg, 0.085 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 30 mg of pure product [Molecular Formula: C69H126N12O13S; Exact Mass: 1362.93; MS (m/z): 1363.72 (M+1)+, 1385.81 (M+Na)+; TLC Rf: 0.15 (ethyl acetate/methanol=5:1); HPLC RT: 12.26 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 35
[(S)-(2-(N-Ethyl-N-isopropylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-Isopropylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (49 mg, 0.034 mmol) and acetaldehyde (100 μl, 37% in water) were mixed with chloroform (10 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (22 mg, 0.085 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 37 mg of pure product [Molecular Formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1377.84 (M+1)+; TLC Rf: 0.15 (ethyl acetate/methanol=5/1); HPLC RT: 12.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 36
[(S)-(2-(N-Isobutylamino-N-isopropyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-isopropylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and isobutyraldehyde (91 μl, 10 mmol) were dissolved in chloroform (30 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (0.13 g, 0.50 mmol) in portion. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 19 mg of pure product [Molecular Formula: C72H132N12O13S; Exact Mass: 1404.98; MS (m/z): 1405.89 (M+1)+, 1427.94 (M+Na)+; TLC Rf: 0.25 (ethyl acetate/methanol=5/1); HPLC RT: 14.46 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 37
[(S)-(2-(N,N-Diisobutylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-Aminoethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (42 mg, 0.032 mmol) and isobutyraldehyde (15 μl, 0.165 mmol) were dissolved in chloroform (10 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (21 mg, 0.080 mmol) in portions. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 23 mg of pure product [Molecular Formula: C73H134N12O13S; Exact Mass: 1418.99; MS (m/z): 1419.73 (M+1)+, 1441.87 (M+Na)+; TLC Rf: 0.36 (ethyl acetate/methanol=5:1); HPLC RT: 14.46 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 38
[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(Amino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.45 g, 0.34 mmol) and pivalaldehyde (100 μl, 37% in water) were mixed with chloroform (50 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (0.22 g, 0.85 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 11 mg of pure product [Molecular Formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1377.72 (M+1)+, 1399.82 (M+Na)+; TLC Rf: 0.15 (ethyl acetate/methanol=5/1); HPLC RT: 12.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 39
[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (49 mg, 0.034 mmol) and formaldehyde (100 μl, 37% in water) were mixed with chloroform (10 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (22 mg, 0.085 mmol. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 31 mg of pure product [Molecular Formula: C71H130N12O13S; Exact Mass: 1390.96; MS (m/z): 1391.71 (M+1)+, 1413.86 (M+Na)+; TLC Rf: 0.25 (ethyl acetate/methanol=5/1); HPLC RT: 13.28 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 40
[(S)-(2-(N-Ethyl-N-neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (46 mg, 0.034 mmol) and acetaldehyde (10 μl, 0.17 mmol) were dissolved in chloroform/methanol, followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (22 mg, 0.085 mmol) in portions. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 28 mg of product [Molecular Formula: C72H132N12O13S; Exact Mass: 1404.98; MS (m/z): 1405.75 (M+1)+, 1427.95 (M+Na)+; TLC Rf: 0.25 (ethyl acetate/methanol=5/1); HPLC RT: 13.65 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 41
[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (260 mg, 0.21 mmol) and 2-morpholinoethanethiol (300 mg, 2.04 mmol) in methanol (30 ml) was added lithium hydroxide (140 mg, 5.83 mmol). The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 102 mg of product [Molecular Formula: C69H124N12O14S; Exact Mass: 1376.91; MS (m/z): 1399.85 (M+Na)+; TLC Rf: 0.30 (dichloromethane/methanol=9/1); HPLC RT: 11.03 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm); 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.68 (d, J=6.6 Hz, 3H), 0.79 (d, J=6.6 Hz, 3H), 0.82 (m, 6H,), 0.85 (d, J=6.6 Hz, 3H), 0.88 (d, J=7.2 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.97-1.00 (m, 9H), 1.08 (d, J=6.6 Hz, 3H), 1.21-1.25 (m, 11H), 1.31 (d, J=7.2 Hz, 3H), 1.39-1.47 (m, 2H), 1.54-1.61 (m, 8H), 1.66-1.70 (m, 2H), 1.75 (m, 1H), 2.01-2.11 (m, 4H), 2.36-2.43 (m, 7H), 2.55-2.59 (m, 2H), 2.67 (m, 8H), 2.93-3.04 (m, 2H), 3.10 (s, 3H), 3.24 (s, 6H), 3.26 (s, 3H), 3.48 (s, 3H), 3.52 (br, 1H), 3.67 (m, 6H), 4.51 (m, 1H), 4.59 (t, J=8.4 Hz, 1H), 4.81 (m, 1H), 4.94-5.00 (m, 2H), 5.04 (t, J=6.6 Hz, 1H), 5.08 (d, J=10.8 Hz, 1H), 5.27-5.31 (m, 1H), 5.33-5.37 (m, 1H), 5.48 (m, 2H), 5.67 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H)].
Example 42
[(S)-(2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.37 g, 0.30 mmol) and 2-(N-piperidino)ethylthiol (0.44 g, 3.00 mmol) were dissolved in methanol (30 ml), followed by adding 10 equivalents of lithium hydroxide. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 0.20 g of product [Molecular Formula: C70H126N12O13S; Exact Mass: 1374.93; MS (m/z): 1375.65 (M+1)+, 1397.80 (M+Na)+; TLC Rf: 0.18 (ethyl acetate/methanol=5/1); HPLC RT: 12.09 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 43
[(S)-2-(N-piperazinylethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (1.37 g, 1.11 mmol) and 2-mercaptoethylpiperazine (0.49 g, 3.33 mmol) were dissolved in methanol (25 ml), followed by adding lithium hydroxide (0.26 g, 11.10 mmol). The mixture was stirred at room temperature overnight. Most of solvent was evaporated under reduced pressure. The residue was mixed with ethyl acetate (60 ml) and saturated sodium bicarbonate solution (60 ml) and separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C69H125N13O13S; Exact Mass: 1375.92; MS (m/z): 1376.55 (M+1)+, 1398.69 (M+Na)+; TLC Rf: 0.11 (dichloromethane/methanol=9:1); HPLC RT: 8.06 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 44
[(S)-(2-(4-Methyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.24 mmol) and 2-(4-methylpiperazino)ethylthiol (0.42 g, 2.62 mmol) were dissolved in methanol (30 ml), followed by adding 10 equivalents of lithium hydroxide. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was dissolved in methylene chloride (30 ml). The dichloromethane solution was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 0.22 g of product [Molecular Formula: C70H127N13O13S; Exact Mass: 1389.94; MS (m/z): 1390.9 (M+1)+; TLC Rf: 0.08 (ethyl acetate/methanol=5/1); HPLC RT: 10.07 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 45
[(S)-(2-(4-Ethyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.24 mmol) and 3-(1-ethyl-4-piperazino)ethylthiol (0.30 g, 1.72 mmol) were dissolved in methanol (15 ml), followed by adding lithium hydroxide (58 mg, 2.41 mmol). The mixture was stirred overnight at room temperature. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=94/6) to give product [Molecular formula: C71H129N13O13S; Exact Mass: 1403.96; MS (m/z): 1404.55 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=85/15); HPLC RT: 8.83 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 46
[(S)-2-(4-Propyl-N-piperazinylethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (80 mg, 0.058 mmol) and propionaldehyde (MW 58.08, d 0.81, 42 μl, 0.580 mmol) were dissolved in dichloromethane (25 ml), followed by adding tetramethylammonium triacetoxyborohydride (153 mg, 0.580 mmol) in portions and acetic acid (3 drops). The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C72H131N13O13S; Exact Mass: 1417.97; MS (m/z): 1418.60 (M+1)+, 1440.79 (M+Na)+; TLC Rf: 0.37 (dichloromethane/methanol=9:1); HPLC RT: 9.61 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 47
[(S)-(2-(4-Isobutyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (80 mg, 0.058 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 53 μl, 0.58 mmol) were dissolved in dichloromethane (25 ml), followed by adding tetramethylammonium triacetoxyborohydride (153 mg, 0.58 mmol) in portions and acetic acid (3 drops). The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C73H133N13O13S; Exact Mass: 1431.99; MS (m/z): 1432.63 (M+1)+, 1454.78 (M+Na)+; TLC Rf: 0.44 (dichloromethane/methanol=9:1); HPLC RT: 10.08 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 48
[(S)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (80 mg, 0.058 mmol) and 2-bromoethanol (FW 124.97, d 1.762, 41 μl, 0.58 mmol) were dissolved in dichloromethane (15 ml), followed by adding sodium carbonate (15.4 mg, 0.15 mmol). The mixture was stirred at room temperature for a weekend. Then the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give 20.8 mg of product [Molecular Formula: C71H129N13O14S; Exact Mass: 1419.95; MS (m/z): 1420.52 (M+1)+, 1442.72 (M+Na)+; TLC Rf: 0.20 (dichloromethane/methanol=9:1); HPLC RT: 8.79 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 49
[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (280 mg, 0.23 mmol) and 2-(N-pyrrolidinyl)ethanethiol (280 mg, 2.14 mmol) in methanol (30 ml) was added lithium hydroxide (114 mg, 4.75 mmol). The reaction mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 126 mg of product [Molecular Formula: C69H124N12O13S; Exact Mass: 1360.91; MS (m/z): 1361.80 (M+1)+; TLC Rf: 0.23 (dichloromethane/methanol=95/5); HPLC RT: 11.59 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 50
[(S)-(2-Hydroxylethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (200 mg, 0.16 mmol) and 2-mercaptoethanol (MW 78.13, d 1.114, 112 μl, 1.60 mmol) were dissolved in methanol (10 ml), followed by adding lithium hydroxide (23 mg, 0.96 mmol). The mixture was stirred at room temperature overnight. Most of solvent was evaporated under reduced pressure. The residue was mixed with ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml) and separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C65H117N11O14S; Exact Mass: 1307.85; MS (m/z): 1308.44 (M+1)+, 1330.68 (M+Na)+; TLC Rf: 0.41 (dichloromethane/methanol=9:1); HPLC RT: 12.61 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 51
[(S)-2-Ethoxyethylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.12 mmol) and 2-ethoxyethanethiol (160 mg, 1.51 mmol) in methanol (10 ml) was added lithium hydroxide (50 mg, 2.08 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=97/3) to give a pure product [Molecular formula: C67H121N11O14S; Exact Mass: 1335.88; MS (m/z): 1336.49 (M+1)+; TLC Rf: 0.43 (dichloromethane/methanol=97/3); HPLC RT: 15.51 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 52
[(S)-(2-(Ethoxycarbonylmethoxy)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [(S)-(2-hydroxyethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.28 g, 0.21 mmol) in benzene (15 ml) were added a solution of sodium hydroxide (0.60 g, 15.00 mmol) in water (1 ml), ethyl bromoacetate (1.50 g, 8.98 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). The mixture was stirred at room temperature for 10 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (15 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=97/3) to give a pure product [Molecular Formula: C69H123N11O16S; Exact Mass: 1393.89; MS (m/z): 1394.48 (M+1)+; TLC Rf: 0.45 (dichloromethane/methanol=95/5); HPLC RT: 15.28 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 53
[(S)-(2-(2-Hydroxyethoxy)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a suspension of [(S)-((ethoxycarbonylmethoxy)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (100 mg, 0.07 mmol) and lithium chloride (15 mg, 0.35 mmol) in methanol (10 ml) was added sodium borohydride (125 mg, 3.29 mmol) in portions. The mixture was stirred overnight at room temperature for 6 hours. Most of solvent was evaporated under reduced pressure. Dichloromethane (50 ml) and water (200 ml) were added and separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give the product [Molecular formula: C67H121N11O15S; Exact Mass: 1351.88; MS (m/z): 1352.46 (M+1)+; TLC Rf: 0.32 (dichloromethane/methanol=95/5); HPLC RT: 12.87 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 54
[(S)-(2-(2-Methoxyethoxy)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (300 mg, 0.24 mmol) and 2-(2-methoxyethoxy)ethanethiol (330 mg, 2.42 mmol) in methanol (20 ml) was added lithium hydroxide (60 mg, 2.50 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=97/3) to give a pure product [Molecular formula: C68H123N11O15S; Exact Mass: 1365.89; MS (m/z): 1366.49 (M+1)+; TLC Rf: 0.37 (dichloromethane/methanol=97/3); HPLC RT: 14.72 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 55
[(S)-(3-Aminopropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (3.00 g, 2.44 mmol) and 3-aminopropanethiol (1.33 g, 14.59 mmol) were dissolved in methanol (80 ml), followed by adding lithium hydroxide (0.35 g, 14.65 mmol). The mixture was stirred at room temperature for a weekend. After removal of solvent, the residue was purified by chromatography using dichloromethane/methanol as eluent to give product [Molecular Formula: C66H120N12O13S; Exact Mass: 1320.88; MS (m/z): 1321.52 (M+1)+, 1343.67 (M+Na)+, TLC Rf: 0.028 (dichloromethane/methanol=5/1); HPLC RT: 10.24 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 56
[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.24 mmol) and 3-(N,N-dimethyl)propylthiol (0.36 g, 2.40 mmol) were dissolved in methanol (25 ml), followed by adding lithium hydroxide (59 mg, 2.44 mmol). The mixture was stirred at room temperature overnight. After removal of solvent, the residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 0.18 g of pure product [Molecular Formula: C68H124N12O13S; Exact Mass: 1348.91; MS (m/z): 1349.70 (M+1)+, 1371.83 (M+Na); TLC Rf: 0.15 (ethyl acetate/methanol=5/1); HPLC RT: 11.53 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 57
[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.24 mmol) and 3-(N,N-dimethyl)propylthiol (0.36 g, 2.44 mmol) were dissolved in methanol (25 ml), followed by adding lithium chloride (59 mg, 2.4 mmol). The mixture was stirred at room temperature overnight. After removal of solvent, the residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 0.30 g of product [Molecular Formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1377.90 (M+1)+, 1399.76 (M+Na)+; TLC Rf: 0.17 (ethyl acetate/methanol=5/1); HPLC RT: 12.06 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 58
[(S)-(3-(N-Isopropylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(3-Aminopropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and acetone (MW 58.08, d 0.791, 42 μl, 0.57 mmol) were dissolved in 10 ml of dichloromethane, followed by adding tetramethylammonium triacetoxyborohydride (74.7 mg, 0.28 mmol) in portions and a few drops of acetic acid. The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C69H126N12O13S; Exact Mass: 1362.93; MS (m/z): 1363.60 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=9/1); HPLC RT: 10.89 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 59
[(S)-(3-(N-Ethyl-N-isopropylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (200 mg, 0.16 mmol) and 3-(N-ethyl-N-isopropylamino)propylthiol (200 mg, 1.25 mmol) in methanol (25 ml) was added lithium hydroxide (89 mg, 3.71 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 88 mg of product [Molecular Formula: C71H130N12O13S; Exact Mass: 1390.96; MS (m/z): 1413.81 (M+Na)+; TLC Rf: 0.40 (dichloromethane/methanol=9/1); HPLC RT: 12.49 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 60
[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(3-Aminopropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 15 μl, 0.17 mmol) were dissolved in dichloromethane (25 ml), followed by adding a few drops of acetic acid and tetramethylammonium triacetoxyborohydride (30 mg, 0.11 mmol) in portions. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution (25 ml) and brine (25 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1477.56 (M+1)+, 1399.71 (M+Na)+; TLC Rf: 0.18 (dichloromethane/methanol=9:1); HPLC RT: 11.70 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 61
[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(3-Aminopropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 15 μl, 0.17 mmol) were dissolved in dichloromethane (25 ml), followed by adding a few drops of acetic acid and tetramethylammonium triacetoxyborohydride (30 mg, 0.11 mmol in portions. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution (25 ml) and brine (25 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C73H134N12O13S; Exact Mass: 1433.01; MS (m/z): 1433.64 (M+1)+, 1455.78 (M+Na)+; TLC Rf: 0.24 (dichloromethane/methanol=95:5); HPLC RT: 14.45 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 62
[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(3-Aminopropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (50 mg, 0.04 mmol) and pivalaldehyde (MW 86.13, d 0.793, 21 μl, 0.19 mmol) were mixed with 20 ml of dichloromethane, followed by adding tetramethylammonium triacetoxyborohydride (24.9 mg, 0.10 mmol) and a few drops of acetic acid. The mixture was stirred at room temperature for 6 hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution (30 ml) and brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C71H130N12O13S; Exact Mass: 1390.96; MS (m/z): 1391.54 (M+1)+, 1413.69 (M+Na)+; TLC Rf: 0.24 (dichloromethane/methanol=5/1); HPLC RT: 13.21 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 63
[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) and 3-(N-piperidinyl)propanethiol (318 mg, 2.00 mmol) in methanol (30 ml) was added lithium hydroxide (96 mg, 4.00 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 135 mg of product [Molecular Formula: C71H128N12O13S; Exact Mass: 1388.94; MS (m/z): 1389.84 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=95/5); HPLC RT: 12.19 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm); 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.68 (d, J=6.0 Hz, 3H), 0.79 (d, J=6.0 Hz, 3H), 0.82-0.86 (m, 9H), 0.88 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.97-1.00 (m, 9H), 1.09 (d, J=6.6 Hz, 3H), 1.21-1.24 (m, 11H), 1.31-1.46 (m, 8H), 1.53 (m, 5H), 1.61 (m, 11H), 1.67-1.70 (m, 2H), 1.74-1.76 (m, 2H), 1.99-2.11 (m, 4H), 2.31-2.35 (m, 4H), 2.37-2.41 (m, 2H), 2.53-2.60 (m, 2H), 2.67 (s, 6H), 2.91-2.98 (m. 2H), 3.09 (s, 3H), 3.24 (s, 6H), 3.26 (s, 3H), 3.48 (s, 3H), 3.56 (m, 1H), 3.65 (m, 1H), 4.51 (m, 1H), 4.58 (t, J=8.4 Hz, 1H), 4.81 (m, 1H), 4.94-5.02 (m, 2H), 5.04 (t, J=6.6 Hz, 1H), 5.08 (d, J=10.8 Hz, 1H), 5.28-5.32 (m, 1H), 5.33-5.37 (m, 1H), 5.49 (m, 2H), 5.67 (dd, J=10.8 Hz and 3.6 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 8.09 (d, J=10.2 Hz, 1H)].
Example 64
[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (213 mg, 0.17 mmol) and 3-(N-pyrrolidinyl)propanethiol (280 mg, 1.93 mmol) in methanol (25 ml) was added lithium hydroxide (94 mg, 3.92 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give 57 mg of product [Molecular Formula: C70H126N12O13S; Exact Mass: 1374.93; MS (m/z): 1375.75 (M+1)+; TLC Rf: 0.23 (dichloromethane/methanol=95/5); HPLC RT: 11.83 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 65
[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (210 mg, 0.17 mmol) and 3-morpholinopropanethiol (300 mg, 1.86 mmol) in methanol (25 ml) was added lithium hydroxide (140 mg, 5.83 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 78 mg of product [Molecular Formula: C70H126N12O14S; Exact Mass: 1390.92; MS (m/z): 1413.77 (M+Na)+; TLC Rf: 0.33 (dichloromethane/methanol=9/1); HPLC RT: 11.35 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm); 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.68 (d, J=6.0 Hz, 3H), 0.79 (d, J=5.4 Hz, 3H), 0.82-0.86 (m, 9H), 0.88 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.97-1.00 (m, 9H), 1.09 (d, J=6.6 Hz, 3H), 1.21-1.24 (m, 11H), 1.31 (d, J=7.2 Hz, 3H), 1.38-1.46 (m, 2H), 1.61 (m, 11H), 1.67-1.70 (m, 2H), 1.74-1.76 (m, 2H), 2.03-2.11 (m, 4H), 2.35-2.43 (m, 8H), 2.55-2.63 (m, 2H), 2.67 (s, 6H), 2.91-2.98 (m. 2H), 3.10 (s, 3H), 3.24 (3, 6H), 3.26 (s, 3H), 3.49 (s, 3H), 3.52 (m, 1H), 3.65-3.67 (m, 5H), 4.51 (m, 1H), 4.59 (t, J=8.4 Hz, 1H), 4.81 (m, 1H), 4.94-5.01 (m, 2H), 5.04 (t, J=6.6 Hz, 1H), 5.08 (d, J=12 Hz, 1H), 5.28-5.30 (m, 1H), 5.33-5.37 (m, 1H), 5.49 (m, 2H), 5.67 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H)].
Example 66
[(S)-(3-(N-Morpholino)propylsulfinyl)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxyl)-N-MeLeu]-4-cyclosporin (27 mg, 0.02 mmol) in methanol (5 ml) was added oxone (25 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for one hour. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (20 ml) and saturated sodium bicarbonate solution (5 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give product [Molecular formula: C70H126N12O15S; Exact Mass: 1406.92; MS (m/z): 1407.47 (M+1)+; TLC Rf: 0.23 (dichloromethane/methanol=9/1); HPLC RT: 9.35 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 67
[(S)-(3-(N-Morpholino)propylsulfonyl)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxyl)-N-MeLeu]-4-cyclosporin (30 mg, 0.02 mmol) in methanol (5 ml) were added oxone (40 mg, 0.07 mmol) and water (0.3 ml) at 0° C. The reaction mixture was stirred at room temperature 1 hour. Dichloromethane (30 ml) and cold saturated sodium bicarbonate solution (5 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give product [Molecular formula: C70H126N12O16S; Exact Mass: 1422.91; MS (m/z): 1423.54 (M+1)+; TLC Rf: 0.28 (dichloromethane/methanol=9/1); HPLC RT: 9.38 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 68
[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (280 mg, 0.23 mmol) and 4-(3-thiopropyl)thiomorpholine (280 mg, 1.58 mmol) in methanol (15 ml) was added lithium hydroxide (80 mg, 3.33 mmol). The reaction mixture was stirred at room temperature overnight. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give product [Molecular formula: C70H126N12O13S2; Exact Mass: 1406.90; MS (m/z): 1407.51 (M+1)+; TLC Rf: 0.35 (dichloromethane/methanol=9/1); HPLC RT: 11.18 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 69
[(S)-(3-(4-N-Boc-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (2.95 g, 2.40 mmol) and 1-Boc-4-(3-mercaptopropanyl)piperazine (MW: 260.4, 3.18 g, 5.10 mmol) were dissolved in methanol (75 ml), followed by adding lithium hydroxide (MW: 23.95, 0.35 g, 14.4 mmol). The mixture was stirred at room temperature overnight. After removal of solvent, the residue was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C75H135N13O15S; Exact Mass: 1489.99; MS (m/z): 1490.54 (M+1)+, 1512.63 (M+Na)+; HPLC RT: 12.51 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 70
[(S)-(3-(N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(3-(4-N-Boc-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (1.59 g, 1.07 mmol) was dissolved in methanol (20 ml). Then 4 M hydrochloric acid in dioxane (4 ml) was added. The mixture was stirred at room temperature for one hour. Most of solvent was evaporated under reduced pressure. The residue was mixed ethyl acetate (60 ml) and saturated sodium bicarbonate solution (60 ml) and separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular Formula: C70H127N13O13S; Exact Mass: 1389.94; MS (m/z): 1390.56 (M+1)+, 1412.70 (M+Na)+; TLC Rf: 0.37 (dichloromethane/methanol=5:1); HPLC RT: 8.20 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 71
[(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.24 mmol) and 3-(4-methylpiperazino)propylthiol (MW: 174.31, 0.42 g, 2.44 mmol) were dissolved in methanol (25 ml), followed by adding 10 equivalents of lithium hydroxide (58 mg, 2.40 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 0.20 g of product [Molecular Formula: C71H129N13O13S; Exact Mass: 1403.96; MS (m/z): 1404.9 (M+1)+, 1426.9 (M+Na)+; TLC Rf: 0.10 (ethyl acetate/methanol=5/1); HPLC RT: 10.07 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 72
[(S)-(3-(4-Ethyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and 3-(1-ethyl-4-piperazino)propylthiol (MW: 188.33, 0.20 g, 1.06 mmol) were dissolved in methanol (15 ml), followed by adding lithium hydroxide (MW: 23.95, 48 mg, 20 mmol). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was subject to chromatography using dichloromethane/methanol as eluent to give product [Molecular formula: C72H131N13O13S; Exact Mass: 1417.97; MS (m/z): 1418.58 (M+1)+; TLC Rf: 0.13 (ethyl acetate/methanol=5/1)]. HPLC RT: 8.70 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 73
[(S)-(3-(4-N-n-Propyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(3-(N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and propionaldehyde (MW 58.08, d 0.81, 80 μl, 1.11 mmol) were dissolved in dichloromethane (20 ml), followed by adding acetic acid (5 drops) and tetramethylammonium triacetoxyborohydride (MW: 263.09, 72 mg, 0.28 mmol) in portions. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C73H133N13O13S; Exact Mass: 1431.99; MS (m/z): 1432.61 (M+1)+, 1454.69 (M+Na)+; TLC Rf: 0.24 (dichloromethane/methanol=9:1); HPLC RT: 9.07 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 74
[(S)-(3-(4-N-Isopropyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-3-(N-piperazinylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and 2-bromopropane (MW 123.00, d 1.310, 102 μl, 1.08 mmol) were dissolved in dichloromethane (15 ml), followed by adding sodium carbonate (MW: 105.99, 28.6 mg, 0.27 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C73H135N13O13S; Exact Mass: 1431.99; MS (m/z): 1432.58 (M+1)+, 1454.72 (M+Na)+; TLC Rf: 0.14 (dichloromethane/methanol=9:1); HPLC RT: 8.74 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 75
[(S)-(3-(4-N-Isobutyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-3-(N-piperazinylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (168 mg, 0.12 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 110 μl, 1.21 mmol) were dissolved in dichloromethane (25 ml), followed by adding acetic acid (5 drops) and tetramethylammonium triacetoxyborohydride (79.5 mg, 0.30 mmol) in portions. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C74H135N13O13S; Exact Mass: 1446.00; MS (m/z): 1446.58 (M+1)+, 1468.69 (M+Na)+; TLC Rf: 0.43 (dichloromethane/methanol=9:1); HPLC RT: 9.59 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 76
[(S)-(3-(4-N-Neopentyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-3-(N-piperazinylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and neopentyl bromide (MW 151.05, d 1.195, 136 μl, 1.08 mmol) were dissolved in dichloromethane (20 ml), followed by adding sodium carbonate (MW: 105.99, 28.6 mg, 0.27 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane and methanol as eluent to give product [Molecular Formula: C75H137N13O13S; Exact Mass: 1460.02; MS (m/z): 1460.64 (M+1)+, 1482.72 (M+Na)+; TLC Rf: 0.43 (dichloromethane/methanol=9:1); HPLC RT: 11.25 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 77
[(S)-(2-(Methoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(2-(Methoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (600 mg, 0.49 mmol) and methyl 3-mercaptopropionate (0.54 ml, d 1.085, 4.88 mmol) in methanol (15 ml) was added lithium hydroxide (94 mg, 3.90 mmol). The reaction mixture was stirred at room temperature for 4 hours. Most of solvent was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 270 mg of [(S)-(2-(methoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C67H119N11O15S; Exact Mass: 1349.86. MS (m/z): 1350.43 (M+1)+, 1372.62 (M+Na)] and 260 mg of [(R)-(2-(methoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C67H119N11O15S; Exact Mass: 1349.86. MS (m/z): 1350.42 (M+1)+, 1372.63 (M+Na)+].
Example 78
[(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(2-(Methoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (170 mg, 0.13 mmol) was dissolved in tetrahydrofuran (30 ml), followed by adding cesium chloride (1.00 g, 5.94 mmol) and sodium borohydride (1.00 g, 26.43 mmol). Then 30 ml of methanol was added dropwise to the mixture over 30 minutes. After addition, the mixture was stirred at room temperature one hour. Most solvent was then evaporated under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with dichloromethane/methanol (from 100:0 to 96:4) as eluent to give the 55 mg of pure product [Molecular Formula: C66H119N11O14S; Exact Mass: 1321.87; MS (m/z): 1322.45 (M+1)+, 1344.67 (M+Na)+; TLC Rf: 0.54 (dichloromethane/methanol=9:1); HPLC RT: 13.06 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].




According this method, 28 mg of pure [(R)-(3-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C66H119N11O14S; Exact Mass: 1321.87; MS (m/z): 1322.44 (M+1)+, 1344.69 (M+Na)+; TLC Rf: 0.54 (dichloromethane/methanol=9:1); HPLC RT: 13.02 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)] was obtained.
Example 79
[(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (200 mg, 0.16 mmol) and 3-mercapto-1-propanol (125 mg, 1.36 mmol) in methanol (15 ml) was added lithium hydroxide (80 mg, 3.33 mmol). The reaction mixture was stirred at room temperature overnight. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give product of [(R)-(3-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C66H119N11O14S; Exact Mass: 1321.87; MS (m/z): 1322.53 (M+1)+; TLC Rf: 0.54 (dichloromethane/methanol=9/1); HPLC RT: 13.02 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 80
[(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.31 g, 0.25 mmol) and 1-mercapto-3-methoxypropane (265 mg, 10 mmol) were dissolved in methanol (10 ml), followed by adding 10 equivalents of lithium hydroxide (60 mg). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was dissolved in ethyl acetate (15 ml). The ethyl acetate solution was washed with brine, dried over magnesium sulfite and evaporated under reduced pressure. The residue was subject to a flash chromatography using ethyl acetate/methanol as eluent to give 35 mg of pure product [Molecular formula: C67H121N11O14S; Exact Mass: 1335.88; MS (m/z): 1336.43 (M+1)+, 1358.74 (M+Na)+; TLC Rf: 0.31 (ethyl acetate/methanol=20/1); HPLC RT: 15.21 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 81
[(S)-(3-Methoxy-3-methyl)butylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.12 mmol) and 3-methyl-3-methoxybutanethiol (165 mg, 1.23 mmol) in methanol (10 ml) was added lithium hydroxide (50 mg, 2.08 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=98/2) to give a pure product [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.53 (M+1)+; TLC Rf: 0.33 (ethyl acetate/methanol=98/2); HPLC RT: 16.10 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 82
[(S)-(4-Aminobutylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (1.23 g, 1.0 mmol) and 4-aminobutylthiol (1.06 g, 10.00 mmol) were dissolved in methanol (80 ml), followed by adding 10 equivalents of lithium hydroxide (0.24 g, 10.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was subjected to the flash chromatography using dichloromethane/methanol as eluents to give 0.40 g of product [Molecular formula: C67H122N12O13S; Exact Mass: 1334.89; MS (m/z): 1335.55 (M+1)+, 1357.64 (M+Na)+, TLC Rf: 0.05 (dichloromethane/methanol=5/1); HPLC RT: 10.53 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 83
[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-Aminobuylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (70 mg, 0.05 mmol) and acetaldehyde (MW 44.05, d 0.78, 100 μl, 0.18 mmol)) were dissolved in chloroform (5 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (32.87 mg, 0.125 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular formula: C71H130N12O13S; Exact Mass: 1390.96; MS (m/z): 1391.63 (M+1)+, 1413.79 (M+Na)+; TLC Rf: 0.17 (ethyl acetate/methanol=5/1); HPLC RT: 12.55 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 84
[(S)-(4-(N-Isopropylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-Aminobuylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (60 mg, 0.05 mmol) and acetone (100 μl) were dissolved in chloroform (5 ml), followed by adding tetramethylammonium triacetoxyborohydride (29.5 mg, 0.11 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product. [Molecular formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1377.58 (M+1)+, 1399.79 (M+Na)+; TLC Rf: 0.15 (ethyl acetate/methanol=5/1); HPLC RT: 11.21 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 85
[(S)-(4-(N-Isobutylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-Aminobuylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (80 mg, 0.060 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 27 μl, 0.3 mmol) were dissolved in chloroform (5.0 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (39.4 mg, 0.15 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular formula: C71H130N12O13S; Exact Mass: 1390.96; MS (m/z): 1391.58 (M+1)+, 1413.74 (M+Na)+; TLC Rf: 0.20 (ethyl acetate/methanol=5/1); HPLC RT: 11.99 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 86
[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-Aminobuylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (80 mg, 0.060 mmol) and isobutyraldehyde (MW 72.11, d 0.794, 27 μl, 0.3 mmol) were dissolved in chloroform (5.0 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (39.4 mg, 0.15 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give product [Molecular formula: C75H138N12O13S; Exact Mass: 1447.023; MS (m/z): 1447.63 (M+1)+, 1470.84 (M+Na)+; TLC Rf: 0.25 (ethyl acetate/methanol=5/1); HPLC RT: 13.84 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 87
[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-Aminobuylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (67 mg, 0.05 mmol) and trimethylacetaldehyde (MW 86.13, d 0.781, 27.6 μl, 0.25 mmol) were dissolved in chloroform (5 ml), followed by adding 2.5 equivalents of tetramethylammonium triacetoxyborohydride (32.87 mg, 0.125 mmol). The mixture was stirred at room temperature for two hours. Then the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give 25 mg of pure product [Molecular formula: C72H132N12O13S; Exact Mass: 1404.98; MS (m/z): 1405.54 (M+1)+, 1427.72 (M+Na)+; TLC Rf: 0.17 (ethyl acetate/methanol=5/1); HPLC RT: 12.66 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 88
[(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin and [(R)-(4-hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (213 mg, 0.17 mmol) and 4-mercapto-1-butanol (156 mg, 1.44 mmol) in methanol (25 ml) was added lithium hydroxide (94 mg, 3.92 mmol). The reaction mixture was stirred at room temperature overnight. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subject to a flash chromatography using ethyl acetate/methanol as eluent to give product of isomer A as [(S)-(4-hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin and product of isomer B as [(R)-(4-hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular formula: C67H121N11O14S; Exact Mass: 1335.88; MS (m/z): 1336.44 (M+1)+, 1358.67 (M+Na)+; TLC Rf: 0.38 (dichloromethane/methanol=9/1); TLC Rf (isomer A): 0.25 (ethyl acetate/methanol=20/1, twice development), and TLC Rf (isomer B): 0.20 (ethyl acetate/methanol=20/1, twice development); HPLC RT: 13.57 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 89
[(S)-(3-(Methoxycarbonyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(3-(methoxycarbonyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (1.28 g, 1.04 mmol) and methyl 4-mercaptobutanoate (0.84 g, 6.24 mmol) in methanol (25 ml) was added lithium hydroxide (0.15 g, 6.24 mmol). The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 300 mg of [(S)-(4-(methoxycarbonyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C68H128N11O15S; Exact Mass: 1363.88; MS (m/z): 1364.43 (M+1)+, 1386.64 (M+Na)+; HPLC RT: 15.26 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)] and 220 mg of [(R)-(4-(methoxycarbonyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C68H128N11O15S; Exact Mass: 1363.88; MS (m/z): 1364.43 (M+1)+, 1386.64 (M+Na)+; HPLC RT: 15.13 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 90
[(S)-(4-Hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(4-hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-(Methoxycarbonyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (200 mg, 0.15 mmol) was dissolved in tetrahydrofuran (15 ml), followed by adding cesium chloride (200 mg, 1.18 mmol) and sodium borohydride (300 mg, 7.93 mmol). Then 10 ml of methanol was added dropwise to the mixture over 30 minutes. After addition, the mixture was stirred at room temperature one hour. Most solvent was then evaporated under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with dichloromethane/methanol (from 100:0 to 96:4) as eluent to give 13 mg of pure product [Molecular Formula: C67H121N11O14S; Exact Mass: 1335.88; MS (m/z): 1336.50 (M+1)+, 1358.70 (M+Na)+; TLC Rf: 0.39 (dichloromethane/methanol=9:1); HPLC RT: 13.25 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].




According to this method, 11 mg of pure [(R)-(4-hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin was obtained [Molecular Formula: C67H121N11O14S; Exact Mass: 1335.88; MS (m/z): 1336.50 (M+1)+, 1358.70 (M+Na)+; TLC Rf: 0.39(dichloromethane/methanol=9:1); HPLC RT: 13.28 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 91
[(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (300 mg, 0.244 mmol) and 1-mercapto-4-methoxybutane (MW: 120.21, 292 mg, 10 mmol) were dissolved in methanol (10 ml), followed by adding six equivalents of lithium hydroxide (35 mg). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was dissolved in ethyl acetate (15 ml). The ethyl acetate solution was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subject to the flash chromatography using methylene chloride/methanol as eluent to give 57 mg of pure product [Molecular formula: C66H123N11O14S; Exact Mass: 1349.90; MS (m/z): 1350.45 (M+1)+, 1372.58 (M+Na)+; TLC Rf: 0.30 (methylene chloride/methanol=20/1); HPLC RT: 15.54 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 92
[(S)-(4-(2-(N,N-Diethylamino)ethoxy)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(S)-(4-hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.32 g, 0.24 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.20 g, 30 mmol) in water (2 ml), 2-bromo-N,N-diethylethylamine hydrobromide (MW: 261, 3.80 g, 14.56 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). The reaction mixture was stirred at 30° C. for 48 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give product [Molecular formula: C73H134N12O14S; Exact Mass: 1434.99; MS (m/z): 1435.64 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=9/1); HPLC RT: 12.06 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 93
[(S)-(4-Oxopentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (480 mg, 0.39 mmol) and 5-mercapto-2-pentanone (MW: 118.19, 500 mg, 4.24 mmol) in methanol (30 ml) was added lithium hydroxide (120 mg, 5.00 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate) to give a pure product [Molecular formula: C68H121N11O14S; Exact Mass: 1347.88; MS (m/z): 1348.49 (M+1)+; TLC Rf: 0.46 (dichloromethane/methanol=97/3); HPLC RT: 14.86 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 94
[(S)-(4-Hydroxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [(S)-4-oxopentylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (80 mg, 0.06 mmol) in methanol (5 ml) was added sodium borohydride (36 mg, 0.95 mmol) in portions. After addition, the mixture was stirred at room temperature for one hour. Most of solvent was then evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added. The dichloromethane layer was separated and washed with brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel column with (ethyl acetate/methanol=99/1) to give a pure product [Molecular formula: C68H123N11O14S; Exact Mass: 1349.90; MS (m/z): 1350.49 (M+1)+; TLC Rf: 0.35 (dichloromethane/methanol=97/3); HPLC RT: 14.25 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 95
[(S)-(4-Hydroxy-4-methylpentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [(S)-4-oxopentylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (100 mg, 0.07 mmol) in tetrahydrofuran (25 ml) at 0° C. was added a solution of methylmagnesium bromide in ether (1 ml, 3 M, 3.00 mmol). After addition, the mixture was slowly warmed to room temperature and stirred at room temperature for one and half hour. Then the reaction was quenched by adding aqueous ammonium chloride solution. Dichloromethane (30 ml) and water (30 ml) were added. The dichloromethane layer was separated and washed with brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel column with (ethyl acetate/methanol=99/1) to give a pure product [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.48 (M+1)+; TLC Rf: 0.42 (dichloromethane/methanol=97/3); HPLC RT: 14.74 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 96
[(S)-(4-(Methoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(4-(methoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (1.00 g, 0.81 mmol) and methyl 5-mercaptopentanoate (0.72 g, 4.88 mmol) in methanol (30 ml) was added lithium hydroxide (195 mg, 8.13 mmol). The reaction mixture was stirred at room temperature for 3 hours. Most of solvent was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 210 mg of [(S)-(4-(methoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C69H123N11O15S; Exact Mass: 1377.89; MS (m/z): 1378.49 (M+1)+, 1400.67 (M+Na)+; HPLC RT: 15.72 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)] and 270 mg of [(R)-(4-(methoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C69H123N11O15S; Exact Mass: 1377.89; MS (m/z): 1378.50 (M+1)+, 1400.68 (M+Na)+; HPLC RT: 15.53 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 97
[(S)-(5-Hydroxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-(5-Hydroxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-(M ethoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (170 mg, 0.13 mmol) was dissolved in tetrahydrofuran (30 ml), followed by adding cesium chloride (1.00 g, 5.94 mmol) and sodium borohydride (1.00 g, 26.43 mmol). Then 30 ml of methanol was added dropwise to the mixture over 30 minutes. After addition, the mixture was stirred at room temperature one hour. Most solvent was then evaporated under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with dichloromethane/methanol (from 100:0 to 96:4) as eluent to give 47 mg of pure product of [(S)-(5-hydroxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: C68H123N11O14S; Exact Mass: 1349.90; MS (m/z): 1350.52 (M+1)+, 1372.72 (M+Na)+; TLC Rf: 0.54 (dichloromethane/methanol=9:1); HPLC RT: 14.19 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].




According this method, 48 mg of pure [(R)-(5-hydroxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin was obtained [Molecular Formula: C68H123N11O14S; Exact Mass: 1349.90; MS (m/z): 1350.47 (M+1)+, 1372.71 (M+Na)+; TLC Rf: 0.54 (dichloromethane/methanol=9:1); HPLC RT: 14.14 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 98
[(S)-((5-Hydroxy-5-methyl)hexylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin and [(R)-((5-Hydroxy-5-methyl)hexylthiothio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(S)-(4-(Methoxycarbonyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (340 mg, 0.25 mmol) was dissolved in tetrahydrofuran (10 ml) and put into an ice bath. Then 0.63 ml of 3 M methylmagnesium bromide in ether (1.89 mmol) was added dropwise to the mixture over one hour. After the mixture was stirred 0° C. for two hour, 3 ml of brine was added dropwise to quench the reaction. Most solvent was then evaporated under reduced pressure. Ethyl acetate (10 ml) and water (10 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with dichloromethane/methanol as eluent to give 17 mg of pure product [Molecular Formula: C70H127N11O14S; Exact Mass: 1377.93; MS (m/z): 1378.55 (M+1)+, 1400.79 (M+Na)+; TLC Rf: 0.48 (dichloromethane/methanol=9:1); HPLC RT: 15.22 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].




According to this method, 48 mg of pure [(R)-(5-hydroxy-5-methylhexylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin was obtained [Molecular Formula: C70H127N11O14S; Exact Mass: 1377.93; MS (m/z): 1378.45 (M+1)+, 1400.70 (M+Na)+; TLC Rf: 0.41 (dichloromethane/methanol=9:1); HPLC RT: 15.11 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 99
[(S)—((R)-5-hydroxyhexylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (123 mg, 0.1 mmol) and (R)-1-mercapto-5-hexanol (110 mg, 10 mmol) were dissolved in methanol (10 ml), followed by adding 10 equivalents of lithium hydroxide (14.4 mg). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was dissolved in ethyl acetate (15 ml). The ethyl acetate solution was washed with brine, dried over magnesium sulfite and evaporated under reduced pressure. The residue was subject to a flash chromatography using ethyl acetate/methanol as eluent to give 25 mg of pure product [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.68 (M+1)+, 1386.87 (M+Na)+; TLC Rf: 0.31 (methylene chloride/methanol=20/1); HPLC RT: 14.72 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 100
[(S)-(6-Hydroxylhexylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and 6-mercapto-1-hexanol (MW: 134.24, 0.27 g, 2.00 mmol) were dissolved in methanol (30 ml), followed by adding 10 equivalents of lithium hydroxide (48 mg, 2.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvents, the residue was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subject to the flash chromatography using ethyl acetate/methanol as eluent to give 58 mg of product. [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.59 (M+1)+, 1386.76 (M+Na)+; TLC Rf: 0.28 (ethyl acetate/methanol=20/1); HPLC RT: 14.84 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 101
[(S)-(6-Methoxy-(5-methoxycarbonyl)-6-oxohexylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (500 mg, 0.41 mmol) and dimethyl 4-mercaptobutylmalonate (650 mg, 2.95 mmol) in methanol (80 ml) was added lithium hydroxide (110 mg, 4.58 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was used for next step. [Molecular formula: C72H127N11O17S; Exact Mass: 1449.91; MS (m/z): 1450.37 (M+1)+.
Example 102
[(S)-(6-Hydroxy-(5-hydroxymethyl)hexylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [(S)-(6-methoxy-5-methoxycarbonyl)-6-oxohexylthiomethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.17 mmol) in methanol (40 ml) was added sodium borohydride (350 mg, 9.26 mmol) in portions. The reaction mixture was stirred at room temperature 3 hours. Then most of solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give a pure product [Molecular formula: C70H127N11O15S; Exact Mass: 1393.92; MS (m/z): 1394.45 (M+1)+; TLC Rf: 0.25 (dichloromethane/methanol=95/5); HPLC RT: 12.62 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 103
[(S)-(2-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin and [(R)-(2-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.246 g, 0.2 mmol) and 1-mercapto-2-propanol (0.184 g, 2 mmol) were dissolved in methanol (10 ml), followed by adding 10 equivalents of lithium hydroxide (48 mg). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was dissolved in ethyl acetate (15 ml). The ethyl acetate solution was washed with brine, dried over magnesium sulfite and evaporated under reduced pressure. The residue was subject to a flash chromatography using ethyl acetate/methanol as eluent to give the product of isomer A as [(S)-(2-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin and the product of isomer B as [(R)-(2-Hydroxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular formula: C66H119N11O14S; Exact Mass: 1321.87; MS (m/z): 1322.50 (M+1)+, 1344.76 (M+Na)+; TLC Rf (isomer A): 0.29 (methylene chloride/methanol=20/1, twice development); TLC Rf (isomer B): 0.26 (methylene chloride/methanol=20/1, twice development); HPLC RT: 13.62 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 104
[(S)-(2-Methyl-4-oxypentan-2-ylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (500 mg, 0.41 mmol) and 4-mercapto-4-methyl-2-pentanone (680 mg, 5.15 mmol) in methanol (25 ml) was added lithium hydroxide (160 mg, 6.66 mmol). The reaction mixture was stirred at room temperature for 3 days. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate) to give the product [Molecular formula: C69H123N11O14S; Exact Mass: 1361.90; MS (m/z): 1362.50 (M+1)+; TLC Rf: 0.47 (dichloromethane/methanol=97/3); HPLC RT: 15.51 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 105
[(S)-(2-Methyl-4-hydroxypentan-2-ylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(S)-(2-methyl-4-oxypentan-2-ylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (68 mg, 0.03 mmol) in methanol (5 ml) were added sodium borohydride (36 mg, 0.95 mmol) in portions. After addition, the mixture was stirred at room temperature one hour. Most solvent was then evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The dichloromethane layer was washed with brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel column with dichloromethane/methanol (95/5) as eluent to give the product [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.44 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=97/3); HPLC RT: 15.03 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 106
[(S)-((5-Methoxy-4-methoxycarbonyl)-5-oxopentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (580 mg, 0.47 mmol) and dimethyl 3-mercaptopropylmalonate (MW: 206.26, 600 mg, 2.91 mmol) in methanol (30 ml) was added lithium hydroxide (110 mg, 4.58 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was used for next step. [Molecular formula: C71H125N11O17S; Exact Mass: 1435.90; MS (m/z): 1436.45 (M+1)+.
Example 107
[(S)-((5-Hydroxy-4-hydroxymethyl)pentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [(S)-((5-methoxy-4-methoxycarbonyl)-5-oxopentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (280 mg, 0.19 mmol) in methanol (30 ml) was added sodium borohydride (360 mg, 9.52 mmol) in portions. The reaction mixture was stirred at room temperature 3 hours. Then most of the solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (30 ml) were added and separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give a pure product [Molecular formula: C69H125N11O15S; Exact Mass: 1379.91; MS (m/z): 1380.49 (M+1)+; TLC Rf: 0.23 (dichloromethane/methanol=95/5); HPLC RT: 12.05 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 108
[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.00 g, 25 mmol) in water (2 ml), 2-bromo-N,N-diethylethylamine hydrobromide (MW: 261, 2.80 g, 10.72 mmol) and tetra-n-butylammonium bromide (0.2 g, 0.62 mmol). The mixture was stirred at 30° C. for 20 hours. Then ice water (30 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (25 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 240 mg of product [Molecular Formula: C69H126N12O14; Exact Mass: 1346.95; MS (m/z): 1347.59 (M+1)+; TLC Rf: 0.41 (dichloromethane/methanol=9/1); HPLC RT: 12.20 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 109
[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (300 mg, 0.24 mmol) in benzene (15 ml) were added sodium hydroxide (0.38 g. 9.60 mmol), tetramethylammonium hydroxide pentahydrate (0.44 g, 2.40 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (MW: 184.10, 0.44 g, 2.40 mmol). The mixture was stirred at 30° C. for 36 hours. Then ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with dichloromethane/methanol (95/5) as eluent to give 100 mg of pure product [Molecular Formula: C70H126N12O14; Exact Mass: 1358.95; MS (m/z): 1359.69 (M+1)+, 1381.75 (M+Na)+; TLC Rf: 0.05 (dichloromethane/methanol=20/1); HPLC RT: 12.43 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 110
[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.50 g, 0.40 mmol) in benzene (20 ml) were added sodium hydroxide (0.64 g, 16.00 mmol), tetramethylammonium hydroxide pentahydrate (0.72 g, 4.00 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (MW: 186.08, 0.74 g, 4.00 mmol). The mixture was stirred at 30° C. for a week. Then ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with dichloromethane/methanol (95/5) as eluent to give 60 mg of product [Molecular Formula: C69H124N12O15; Exact Mass: 1360.93; MS (m/z): 1361.63 (M+1)+, 1383.75 (M+Na)+; TLC Rf: 0.10 (dichloromethane/methanol=5:1); HPLC RT: 11.49 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 111
[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.37 g, 0.30 mmol) in benzene (15 ml) were added sodium hydroxide (0.48 g. 12.00 mmol), tetramethylammonium hydroxide pentahydrate (0.54 g, 3.00 mmol) and 3-dimethylaminoethyl chloride hydrochloride (0.43 g, 3.00 mmol). The mixture was stirred at 30° C. for 36 hours. Then ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with dichloromethane/methanol (95/5) as eluent to give 90 mg of pure product [Molecular Formula: C67H122N12O14; Exact Mass: 1318.92; MS (m/z): 1319.70 (M+1)+, 1341.80 (M+Na)+); TLC Rf: 0.05 (dichloromethane/methanol=5:1); HPLC RT: 11.43 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 112
[(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.38 g, 0.30 mmol) in benzene (15 ml) were added sodium hydroxide (0.48 g, 12.00 mmol), tetramethylammonium hydroxide pentahydrate (0.54 g, 3.00 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (0.44 g, 3.00 mmol). The mixture was stirred at 30° C. for 36 hours. Then ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with dichloromethane/methanol (95/5) as eluent to give to give 120 mg of the expected isomer [Molecular Formula: C69H124N12O14; Exact Mass: 1344.94; MS (m/z): 1345.62 (M+1)+, 1367.76 (M+Na)+; TLC Rf: 0.05 (dichloromethane/methanol=10/1); HPLC RT: 12.09 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 113
[(R)-(Ethoxycarbonylmethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.36 g, 0.29 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (0.60 g, 15.00 mmol) in water (1 ml), ethyl bromoacetate (1.60 g, 9.58 mmol) and tetra-n-butylammonium bromide (0.20 g, 0.62 mmol). The mixture was stirred at room temperature for 10 hours. After diluted with ice water, the mixture was separated. The aqueous layer was extracted with dichloromethane (15 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give the product [Molecular formula: C67H119N11O16; Exact Mass: 1333.88; MS (m/z): 1334.50 (M+1)+; TLC Rf: 0.35 (dichloromethane/methanol=95/5); HPLC RT: 15.16 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% NH4OAc in water; operation temperature: 64° C.; Detector: 210 nm)].
Example 114
[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-(ethoxycarbonylmethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.23 g, 0.17 mmol) in methanol (30 ml) were added lithium chloride (0.30 g, 7.14 mmol) and sodium borohydride (0.66 g, 17.46 mmol) in portions. After addition, the mixture was stirred at room temperature overnight. Most solvent was then evaporated under reduced pressure. Ethyl acetate (50 ml) and water (50 ml) were added. The ethyl acetate layer was separated and washed with brine (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel column with (dichloromethane/methanol=95/5) to give the product [Molecular formula: C65H117N11O15; Exact Mass: 1291.87; MS (m/z): 1292.51 (M+1)+; TLC Rf: 0.28 (dichloromethane/methanol=9/1); HPLC RT: 12.55 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 115
[(R)-(2-(1,3-Dioxan-2-yl)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-Hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (5.00 g, 4.01 mmol) was dissolved in benzene (100 ml). 2-(2-Bromoethyl)-1,3-dioxane (7.82 g, 40.10 mmol), tetra-n-butylammonium bromide (0.99 g, 3.09 mmol), sodium hydroxide (3.21 g, 8.02 mmol) and water (3.3 ml) were added. The reaction mixture was stirred at 35° C. for nine hours. And the stirring was continued overnight at room temperature. Then 50 ml of brine was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel with hexane/acetone as eluent, 1.50 g of product obtained [Molecular Formula: C69H123N11O16; Exact Mass: 1361.91; (m/z): 1362.64 (M+1)+, 1384.85 (M+Na)+].
Example 116
[(R)-(2-Formylethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(2-(1,3-Dioxan-2-yl)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (1.29 g, 0.95 mmol) was dissolved in dioxane (25 ml), followed by adding hydrochloric acid solution (1 N, 25 ml). The reaction mixture was stirred overnight at room temperature. Most of dioxane was evaporated under reduced pressure. Then the aqueous layer was extracted with ethyl acetate (25 ml×2). The combined ethyl acetate layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel with hexane/acetone as eluent to give 600 mg of product [Molecular Formula: C66H117N11O15; Exact Mass: 1303.87; MS (m/z): 1304.59 (M+1)+, 1326.78 (M+Na)+; HPLC RT: 14.2 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 117
[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(2-Formylethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (300 mg, 0.23 mmol) was dissolved in dichloromethane (15 ml). Morpholine (100 mg, 1.15 mmol) and tetramethylammonium triacetoxyborohydride (302 mg, 1.15 mmol) were added. The reaction mixture was stirred overnight at room temperature. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 105 mg of pure product was obtained [Molecular Formula: C70H126N12O15; Exact Mass: 1374.95; MS (m/z): 1375.70 (M+1)+, 1397.80 (M+Na)+; TLC Rf: 0.37 (dichloromethane/methanol=9/1); HPLC RT: 12.2 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 118
[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(2-Formylethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (200 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml). Pyrrolidine (95 mg, 1.34 mmol) and tetramethylammonium triacetoxyborohydride (353 mg, 1.34 mmol) were added. The reaction mixture was stirred overnight at room temperature. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 50 mg of pure product was obtained [Molecular Formula: C70H126N12O14; Exact Mass: 1358.95; MS (m/z): 1359.74 (M+1)+, 1381.79 (M+Na)+; TLC Rf: 0.40 (dichloromethane/methanol=9/1); HPLC RT: 12.7 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 119
[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(2-Formylethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (200 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml). Piperidine (114 mg, 1.34 mmol) and tetramethylammonium triacetoxyborohydride (353 mg, 1.34 mmol) were added. The reaction mixture was stirred overnight at room temperature. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 43 mg of product was obtained [Molecular Formula: C71H128N12O14; Exact Mass: 1372.97; (m/z): MS (m/z): 1373.79 (M+1)+, 1395.86 (M+Na)+; TLC Rf: 0.27 (dichloromethane/methanol=9/1); HPLC RT: 17.8 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 120
[(R)-(3-(3-Hydroxy-2,2-dimethylpropylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(2-Formylethoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (100 mg, 0.08 mmol) was dissolved in dichloromethane (15 ml). 3-Amino-2,2-dimethyl-1-propanol (40 mg, 0.39 mmol) and tetramethylammonium triacetoxyborohydride (100 mg, 0.39 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours. Then sodium bicarbonate saturated solution (30 ml) and dichloromethane (15 ml) were added and the mixture was separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 10 mg of pure product was obtained [Molecular Formula: C71H130N12O15; Exact Mass: 1390.98; MS (m/z): 1391.64 (M+1)+, 1413.77 (M+Na)+; TLC Rf: 0.37 (dichloromethane/methanol=9/1); HPLC RT: 11.46 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 121
[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.38 g, 0.30 mmol) in benzene (15 ml) were added sodium hydroxide (0.48 g, 12.00 mmol), tetramethylammonia hydroxide (0.54 g, 3.0 mmol) and 3-dimethylaminoethyl chloride hydrochloride (0.43 g, 3.00 mmol). The mixture was stirred at 30° C. for 36 hours. Then ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel with dichloromethane/methanol (95/5) as eluent to give to give 70 mg of pure product [Molecular Formula: C68H124N12O14; Exact Mass: 1332.94. MS (m/z): 1333.64 (M+1)+, 1355.73 (M+Na)+; TLC Rf: 0.04 (dichloromethane/methanol=5/1); HPLC RT: 11.78 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 122
[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in benzene (15 ml) were added a solution of sodium hydroxide (400 mg, 10.00 mmol) in water (0.5 ml), 3-diethylaminepropyl chloride hydrochloride (500 mg, 2.69 mmol) and tetramethylammonium hydroxide pentahydrate (430 mg, 2.41 mmol). The mixture was stirred at 32° C. for 4 days. Then ice water (30 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give 120 mg of product [Molecular Formula: C70H128N12O14; Exact Mass: 1360.97; MS (m/z): 1361.72 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=9/1); HPLC RT: 16.71 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 123
[(R)-(3-Hydroxypropoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.00 g, 25 mmol) in water (2 ml), 2-(3-bromopropoxy)tetrahydro-2H-pyran (2.50 g, 11.21 mmol) and tetra-n-butylammonium bromide (0.2 g, 0.62 mmol). The mixture was stirred at 30° C. for 4 hours. Then ice water (30 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (25 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give the product [Molecular Formula: C66H119N11O15; Exact Mass: 1305.89; MS (m/z): 1306.46 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=9/1); HPLC RT: 12.94 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 124
[(R)-(4-Acetoxybutyloxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (0.34 g, 0.27 mmol) in benzene (10.0 ml) were added 4-bromobutyl acetate (1.56 ml, d 1.348, 10.81 mmol), tetra-n-butylammonium bromide (0.30 g, 0.94 mmol) and sodium hydroxide (0.70 g, 17.6 mmol). The mixture was stirred at room temperature for two hours and then washed with brine, dried over magnesium sulfate. After removal of solvent under reduced pressure, the residue was purified by chromatography on silica gel to give pure product [Molecular formula: C69H123N11O16; Exact Mass: 1361.91; MS (m/z): 1362.51 (M+1)+, 1385.77 (M+Na)+].
Example 125
[(R)-(4-Hydroxylbutoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[(R)-(4-Acetoxybutyloxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (49 mg, 0.036 mmol) was dissolved in methanol (5 ml). Water (3 ml) and potassium carbonate (99 mg, 0.72 mmol) were added and the mixture was stirred for two hours. After removal of methanol, the residue was dissolved in ethyl acetate (6 ml). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate/methanol as eluent to give 22 mg of the pure product [Molecular formula: C67H121N11O15; Exact Mass: 1319.90; MS (m/z): 1320.58 (M+1)+, 1342.78 (M+Na)+; TLC Rf: 0.20 (methylene/methanol=25/1); HPLC RT: 13.62 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 126
[(R)-(4-Methoxylbutoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(S)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.624 g, 0.50 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (1.40 g, 35 mmol) in water (2 ml), 1-bromo-4-methoxybutane (0.84 g, 5.0 mmol) and tetra-n-butylammonium bromide (0.563 g, 1.75 mmol). The mixture was stirred at room temperature overnight and then at 30° C. for 4 hours. Then ice water (30 ml) was added and separated. The aqueous layer was extracted with dichloromethane (25 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=20:1) to give 50 mg of product [Molecular formula: C68H123N11O15; Exact Mass: 1333.92; MS (m/z): 1334.44 (M+1)+, 1356.67 (M+Na); TLC Rf: 0.33 (dichloromethane/methanol=20/1); HPLC RT: 15.52 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% NH4OAc in water; operation temperature: 64° C.; Detector: 210 nm)].
Example 127
[(R)-(5-Hydroxypentyloxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) in benzene (30 ml) were added a solution of sodium hydroxide (1.00 g, 25 mmol) in water (2 ml), 5-bromopentyl acetate (2.20 g, 10.53 mmol) and tetra-n-butylammonium bromide (0.2 g, 0.62 mmol). The mixture was stirred at 30° C. for 10 hours. Then ice water (30 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (25 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give the product [Molecular Formula: C68H123N11O15; Exact Mass: 1333.92; MS (m/z): 1334.46 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=95/5); HPLC RT: 14.22 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 128
[(γ-(Methylthio)methoxy)-NMeLeu]-4-cyclosporin




To a solution of [(γ-hydroxy)-N-MeLeu]-4-cyclosporin (4.50 g, 3.70 mmol) in anhydrous dimethyl sulfoxide (25 ml) was added acetic anhydride (15 ml). The reaction mixture was stirred at room temperature for 17 hours. After diluted with ethyl acetate (75 ml), the mixture was washed with saturated sodium bicarbonate water solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel chromatography with dichloromethane/methanol (98/2) as eluant to give 2.35 g of [(γ-methylthio)methoxy-N-MeLeu]-4-cyclosporin [Molecular Formula: C64H115N11O13S; Exact Mass: 1277.84; MS (m/z): 1300.70 (M+Na)+; TLC Rf: 0.30 (dichloromethane/methanol=95/5); HPLC RT: 19.57 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 129
[γ-(Methoxy)-NMeLeu]-4-cyclosporin




To a solution of [γ-(Methylthio)methoxy-N-MeLeu]-4-cyclosporin (1.20 g, 0.94 mmol) in anhydrous tetrahydrofuran (40 ml) was added Raney Ni ( ̃2 g). The resulting suspension was stirred and heated to 60° C. for 30 minutes and the reaction was monitored by LC-MS. The reaction mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was collected and evaporated under reduced pressure. The residue was purified by chromatography using eluant of ethyl acetate/methanol (97.5/2.5) to give 0.60 g of product [Molecular Formula: C63H113N11O13; Exact Mass: 1231.85; MS (m/z): 1232.70 (M+1)+; TLC Rf: 0.46 (dichloromethane/methanol=95/5); HPLC RT: 20.63 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 130
[α-Carboxy-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




n-Butyllithium (2.8 M in tetrahydrofuran/hexane, 5.00 ml, 14.00 mmol) was added to a solution of diisopropylamine (1.44 g, 14.30 mmol) in tetrahydrofuran (30 ml) at −78° C. under nitrogen atmosphere. After the mixture was stirred for one and half hour, a solution of [γ-(methoxy)-N-MeLeu]-4-cyclosporin (1.20 g, 0.97 mmol) in tetrahydrofuran (6 ml) was added slowly. The stirring was continued at −78° C. for 2 hours. Then carbon dioxide gas was bubbled into the reaction mixture for one hour. The mixture was allowed to warm to room temperature slowly and stirred for another 3 hours. After most of solvent was evaporated under reduced pressure, dichloromethane (30 ml) and water (30 ml) were added. The PH of the mixture was adjusted to around 5 by adding aqueous citric acid. The mixture was separated, and the dichloromethane layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.20 g of crude product used for next step [Molecular Formula: C64H113N11O15; Exact Mass: 1275.84; MS (m/z): 1298.53 (M+Na)+].
Example 131
[α-Methoxycarbonyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a mixture of [α-carboxy]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (1.20 g. 0.94 mmol) and potassium carbonate (0.80 g, 5.79 mmol) in N,N-dimethylformamide (25 ml) was added iodomethane (0.80 g, 5.63 mmol). The mixture was stirred at room temperature overnight. Dichloromethane (75 ml) and water (30 ml) were added and the mixture was separated. The dichloromethane layer was washed with water (25 ml) and brine (25 ml), dried magnesium sulfate and concentrated under reduced pressure to give 1.10 g of crude product [Molecular Formula: C65H115N11O15; Exact Mass: 1289.86; MS (m/z): 1312.72 (M+Na)+].
Example 132
[(R)-α-Hydroxymethyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a suspension of [α-methoxycarbonyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (1.10 g, 0.85 mmol) and lithium chloride (1.00 g, 23.53 mmol) in methanol (80 ml) was added sodium borohydride (2.00 g, 52.91 mmol) in portions. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Dichloromethane (50 ml) and water (30 ml) were added and the mixture was separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 310 mg of product [Molecular Formula: C64H115N11O14; Exact Mass: 1261.86; MS (m/z): 1262.68 (M+1)+].
Example 133
[α-Methylene-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin was prepared according to the method described in Example 28 [Molecular Formula: C64H113N11O13; Exact Mass: 1243.85; MS (m/z): 1244.57 (M+1)+; TLC Rf: 0.34 (hexane/acetone=6/1); HPLC RT: 17.10 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid), operation temperature: 64° C.; detector: 210 nm].
Example 134
[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (0.24 g, 0.19 mmol) and 2-(N,N-dimethylamino)ethylthiol hydrochloride (0.27 g, 1.91 mmol) was dissolved in methanol (30 ml), followed by adding 20 equivalents of lithium hydroxide (46 mg, 1.90 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using methylene chloride/methanol (96/4) as eluent to give 0.11 g of pure product [Molecular Formula: C68H124N12O13S; Exact Mass: 1348.93; MS (m/e): 1349.85 (M+1)+, 1371.81 (M+Na)+; TLC Rf: 0.20 (ethyl acetate/methanol (5:1); HPLC RT: 12.42 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 135
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (280 mg, 0.23 mmol) and 2-diethylaminoethanethiol hydrochloride (570 mg, 3.37 mmol) in methanol (15 ml) was added lithium hydroxide (142 mg, 5.92 mmol). The reaction mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 110 mg of product [Molecular Formula: C70H128N12O13S; Exact Mass: 1376.94; MS (m/z): 1377.67 (M+1)+; TLC Rf: 0.35 (dichloromethane/methanol=95/5); HPLC RT: 13.17 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 136
[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (230 mg, 0.18 mmol) and 2-(N-pyrrolidinyl)ethanethiol (340 mg, 2.59 mmol) in methanol (15 ml) was added lithium hydroxide (120 mg, 5.00 mmol). The reaction mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (30 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 55 mg of product [Molecular Formula: C70H126N12O13S; Exact Mass: 1374.93; MS (m/z): 1375.57 (M+1)+; TLC Rf: 0.29 (dichloromethane/methanol=95/5); HPLC RT: 12.90 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 137
[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) and 2-morpholinoethanethiol (260 mg, 1.76 mmol) in methanol (15 ml) was added lithium hydroxide (120 mg, 5.00 mmol). The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated under reduced pressure. Dichloromethane (60 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 70 mg of product [Molecular Formula: C70H126N12O14S; Exact Mass: 1390.92; MS (m/z): 1391.58 (M+1)+; TLC Rf: 0.38 (dichloromethane/methanol=9/1); HPLC RT: 12.48 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 138
[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and 3-(N,N-dimethylamino)propylthiol (0.24 g, 2.00 mmol) were dissolved in methanol (20 ml), followed by adding 10 equivalents of lithium hydroxide (48 mg, 2.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using methylene chloride/methanol as eluent to give 80 mg of pure product [Molecular Formula: C69H126N12O13S; Exact Mass: 1362.93; MS (m/e): 1363.70 (M+1)+. TLC Rf: 0.20 (ethyl acetate/methanol=10/1); HPLC RT: 12.82 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 139
[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) and 3-(N,N-diethylamino)propylthiol (0.30 g, 2.00 mmol) were dissolved in methanol (20 ml), followed by adding 10 equivalents of lithium hydroxide (48 mg, 2.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using methylene chloride/methanol as eluent to give 120 mg of pure product [Molecular Formula: C71H130N12S; Exact Mass: 1390.96; MS (m/e): 1391.64 (M+1)+, 1413.79 (M+Na)+; TLC Rf: 0.25 (ethyl acetate/methanol=10/1); HPLC RT: 13.57 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 140
[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (0.37 g, 0.30 mmol) and 3-(N-piperidino)propylthiol (0.48 g, 3.00 mmol) were dissolved in methanol (30 ml), followed by adding 10 equivalents of lithium hydroxide (72 mg, 3.00 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using methylene chloride/methanol as eluent to give 60 mg of pure product [Molecular Formula: C72H130N12O13S; Exact Mass: 1402.96; MS (m/e): 1403.69 (M+1)+, 1425 (M+Na)+; TLC: Rf: 0.3 (ethyl acetate/methanol=10/1); HPLC RT: 13.59 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 141
[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (280 mg, 0.23 mmol) and 3-(N-pyrrolidinyl)propanethiol (350 mg, 2.41 mmol) in methanol (15 ml) was added lithium hydroxide (120 mg, 5.00 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (25 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=94/6) to give 47 mg of product [Molecular Formula: C71H128N12O13S; Exact Mass: 1388.94; MS (m/z): 1389.68 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=95/5); HPLC RT: 13.25 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 142
[(S)-(3-(N-Morphlino)propylthio)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [α-Methylene-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (320 mg, 0.26 mmol) and 3-morpholinopropanethiol (600 mg, 3.73 mmol) in methanol (25 ml) was added lithium hydroxide (140 mg, 5.83 mmol). The reaction mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Dichloromethane (60 ml) and water (25 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 58 mg of product [Molecular Formula: C71H128N12O14S; Exact Mass: 1404.94; MS (m/z): 1405.52 (M+1)+; TLC Rf: 0.39 (dichloromethane/methanol=9/1); HPLC RT: 15.96 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 143
[(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin




[(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (100 mg, 0.075 mmol) was dissolved in of benzene (3 ml), followed by adding 3.5 equivalents of tetrabutylammonium bromide, 75 equivalents of 50% of sodium hydroxide and iodomethene (0.425 g. 3.00 mol). The mixture was stirred overnight at room temperature and diluted with benzene (10 ml). The organic mixture was washed with brine, dried over magnesium sulfite and evaporated under reduced pressure. The residue was subject to a flash chromatography using ethyl acetate/methanol as eluent to give 25 mg of product [Molecular formula: C69H125N11O14S; Exact Mass: 1363.91; MS (m/z): 1364.35 (M+1)+, 1386.70 (M+Na)+; TLC Rf: 0.38 (ethyl acetate/methanol=20/1); HPLC RT: 16.72 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temp: 64° C.; Detector: 210 nm)].
Example 144
[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (0.20 g, 0.16 mmol) in benzene (10 ml) were added a solution of sodium hydroxide (0.48 g, 12.00 mmol) in water (1 ml), 2-bromo-N,N-diethylethylamine hydrobromide (1.10 g, 4.21 mmol) and tetra-n-butylammonium bromide (0.10 g, 0.31 mmol). The mixture was stirred at 35° C. for 40 hours. Ice water (10 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 36 mg of product [Molecular Formula: C70H128N12O14; Exact Mass: 1360.97; MS (m/z): 1383.74 (M+Na)+; TLC Rf: 0.32 (dichloromethane/methanol=95/5); HPLC RT: 13.66 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm); 1H NMR spectrum (600 MHz, CDCl3, δ in ppm): 0.65 (d, J=4.8 Hz, 3H), 0.82 (m, 9H), 0.87 (m, 6H), 0.91 (d, J=6. Hz, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.98-1.01 (m, 15H), 1.07 (d, J=6.6 Hz, 3H), 1.11 (s, 6H), 1.23 (m, 6H), 1.33 (d, J=7.2 Hz, 3H), 1.39-1.47 (m, 2H), 1.53-1.58 (m, 4H), 1.6 (m, 3H), 1.67-1.75 (m, 3H), 1.98-2.12 (m, 4H), 2.43-2.48 (m, 3H), 2.50-2.54 (m, 4H), 2.60 (t, J=6.0 Hz, 2H), 2.67 (s, 3H), 2.68 (s, 3H), 3.07 (s, 3H), 3.10 (s, 3H), 3.12 (s, 3H), 3.24 (s, 3H), 3.26 (s, 3H), 3.48 (m, 4H), 3.52-3.56 (m, 1H), 3.60-3.62 (m, 1H), 3.67-3.70 (m, 1H), 3.80 (m, 1H), 4.06 (t, J=9.6 Hz, 1H), 4.52 (m, 1H), 4.57 (m, 1H), 4.80 (m, 1H), 4.91 (t, J=7.8 Hz, 1H), 5.04 (m, 3H), 5.11 (d, J=11.4 Hz, 1H), 5.28-5.34 (m, 2H), 5.50 (d, J=7.2 Hz, 1H), 5.67 (m, 1H), 7.10 (d, J=7.8 Hz 1H), 7.48 (d, J=7.80 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.91 (d, J=10.2 Hz, 1H)].
Example 145
[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 2-dimethylaminoethyl chloride hydrochloride (570 mg, 3.96 mmol). The mixture was stirred at 40 to 50° C. for two days. Sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 2-dimethylaminoethyl chloride hydrochloride (570 mg, 3.96 mmol) were added and the mixture was kept stirring at 40 to 50° C. for another two days. Another portion of 2-dimethylaminoethyl chloride hydrochloride (1.14 g, 7.91 mmol) was added and the stirring was continued at 40 to 50° C. for one more day. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. Then the aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml). The resulting ethyl acetate phase was washed with acetic acid solution (5 ml in 10 ml water) and sodium bicarbonate saturated solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 21 mg product was obtained [Molecular Formula: C68H124N12O14; Exact Mass: 1332.94; MS (m/z): 1333.75 (M+1)+, 1355.87 (M+Na)+; TLC Rf: 0.22 (dichloromethane/methanol=9/1); HPLC RT: 17.3 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)]
Example 146
[(R)-(2-(N-Morphlino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in benzene (20 ml) was added a solution of sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), followed by tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 2-(4-morpholinyl)ethyl chloride hydrochloride (737 mg, 3.96 mmol). The mixture was stirred at 40 to 50° C. for two days. Sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 2-(4-morpholinyl)ethyl chloride hydrochloride (737 mg, 3.96 mmol) were added and the mixture was kept stirring at 40 to 50° C. for another two days. Another portion of 2-(4-morpholinyl)ethyl chloride hydrochloride (1.47 g, 7.91 mmol) was added and the stirring was continued at 40 to 50° C. for two more days. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. Then the aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml). And the resulting ethyl acetate phase was washed with acetic acid solution (5 ml in 10 ml water) and sodium bicarbonate saturated solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 45 mg product was obtained [Molecular Formula: C70H126N12O15; Exact Mass: 1374.95; MS (m/z): 1375.63 (M+1)+, 1397.79 (M+Na)+; TLC Rf: 0.42 (dichloromethane/methanol=9/1); HPLC RT: 12.9 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)]
Example 147
[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporine




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 3-dimethylaminopropyl chloride hydrochloride (626 mg, 3.96 mmol). The mixture was stirred at 40 to 50° C. for two days. Sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 3-dimethylaminopropyl chloride hydrochloride (626 mg, 3.96 mmol) were added and the mixture was kept stirring at 40 to 50° C. for another two days. Another portion of 3-dimethylaminopropyl chloride hydrochloride (1.25 g, 7.91 mmol) was added and the stirring was continued at 40 to 50° C. for one more day. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. Then the aqueous layer was extracted with ethyl acetate (25 ml×2). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml). And the resulting ethyl acetate phase was washed with acetic acid solution (5 ml in 10 ml water) and sodium bicarbonate saturated solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 36 mg product was obtained [Molecular Formula: C69H126N12O14; Exact Mass: 1346.95; MS (m/z): 1347.65 (M+1)+, 1369.74 (M+Na)+; TLC Rf: 0.21 (dichloromethane/methanol=9/1). HPLC RT: 18.8 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)].
Example 148
[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-methoxy)-NMeLeu]-4-cyclosporine




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin (250 mg, 0.20 mmol) in benzene (20 ml) was added a solution of sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), followed by adding tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 3-diethylaminopropyl chloride hydrochloride (737 mg, 3.96 mmol). The mixture was stirred at 40 to 50° C. for two days. Sodium hydroxide (633 mg, 15.85 mmol) in water (0.70 ml), tetramethylammonium hydroxide pentahydrate (720 mg, 3.96 mmol) and 3-diethylaminopropyl chloride hydrochloride (737 mg, 3.96 mmol) were added and the mixture was kept stirring at 40 to 50° C. for another two days. Another portion of 3-diethylaminopropyl chloride hydrochloride (1.47 g, 7.91 mmol) was added and the stirring was continued at 40 to 50° C. for two more days. Sodium bicarbonate saturated solution (30 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (25 ml×2). Then the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml). And the resulting ethyl acetate phase was washed with acetic acid solution (5 ml in 10 ml water) and sodium bicarbonate saturated solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. After purified on silica gel, 38 mg product was obtained [Molecular Formula: C71H130N12O14; Exact Mass: 1374.98; MS (m/z): 1375.70 (M+1)+, 1397.80 (M+Na)+; TLC Rf: 0.24 (dichloromethane/methanol=9/1); HPLC RT: 19.6 min (C8 reverse phase column: 250 mm; acetonitrile/0.077% ammonium acetate in water; operation temperature: 64° C.; detector: 210 nm)]
Example 149
[α-Methylene-Sar]-3-[(γ-methylthiomethoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methylthiomethoxy)-N-MeLeu]-4-cyclosporin was prepared according to the method described in Example 28. The product was purified by chromatography on silica gel (ethyl acetate/methanol) [Molecular Formula: C65H115N11O13S; Exact Mass: 1289.84; MS (m/z): 1290.70 (M+1)+, 1312.67 (M+Na)+].
Example 150
[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[(γ-methylthio)methoxy-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methylthiomethoxy)-N-MeLeu]-4-cyclosporin (0.32 g, 0.25 mmol) and 2-(N,N-dimethyl)ethanethiol (0.26 g, 2.50 mmol) were dissolved in methanol (20 ml), followed by adding 24 equivalents of triethylamine. The mixture was stirred overnight. After removal of solvent, the residue was subject to chromatography using dichloromethane/methanol as eluent to give 0.14 g of pure product [Molecular Formula, C69H126N12O13S2; Exact Mass: 1394.90; MS (m/z): 1395.70 (M+1)+, 1417.68 (M+Na)+; TLC Rf: 0.10 (ethyl acetate/methanol=10:1); HPLC RT: 13.30 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 151
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-methylthio)methoxy-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-methylthiomethoxy)-N-MeLeu]-4-cyclosporin (0.27 g, 0.21 mmol) and 2-(N,N-diethyl)ethanethiol (0.28 g, 2.10 mmol) were dissolved in methanol (20 ml), followed by adding 24 equivalents of triethylamine. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give 0.17 g of pure product [Molecular Formula, C71H130N12O13S2; Exact Mass: 1422.93; MS (m/z): 1423.70 (M+1)+, 1445.67 (M+Na)+; TLC Rf: 0.35 (ethyl acetate/methanol=10:1); HPLC RT: 13.95 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 152
[γ-Ethoxymethoxy-NMeLeu]-4-cyclosporin




To a solution of [(γ-hydroxy)-N-MeLeu]-4-cyclosporin (1.20 g, 0.99 mmol) in dichloromethane (80 ml) was added diisopropylethylamine (FW 129.25, d 0.742, 1.32 ml, 0.98 g, 7.60 mmol), followed by adding chloromethyl ethyl ether (FW 94.54, d 1.02, 2.22 ml, 2.27 g, 24 mmol) dropwise. The mixture was stirred overnight at room temperature and TLC was used to monitor the completion of the reaction. The reaction mixture was washed with 1 N hydrochloric acid, saturated sodium bicarbonate water solution and brine. After dried over magnesium sulfate, the mixture was evaporated under reduced pressure to give a yellowish oil, which was further purified by flash chromatography using dichloromethane/methanol as eluent to give 0.95 g of the product [Molecular Formula: C65H117N11O14; Exact Mass: 1275.88; MS (m/z): 1276.70 (M+H)+, 1298.70 (M+Na)+; TLC Rf: 0.37 (ethyl acetate)].
Example 153
[α-Methylene-Sar]-3-[(γ-ethoxymethoxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-ethoxymethoxy)-N-MeLeu]-4-cyclosporin was prepared according to the method described in Example 28. The product was purified by chromatography on silica gel with ethyl acetate/methanol as eluent [Molecular Formula: C66H117N11O14; Exact Mass: 1287.68; MS (m/z): 1288.72 (M+1)+, 1310.70 (M+Na)+].
Example 154
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-ethoxy)methoxy-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-ethoxymethoxy)-N-MeLeu]-4-cyclosporin (0.27 g, 0.21 mmol) and 2-(N,N-diethyl)ethanethiol (0.28 g, 2.1 mmol) were dissolved in methanol (20 ml), followed by adding 12 equivalents of triethylamine. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give 90 mg of pure product [Molecular Formula: C72H132N12O14S; Exact Mass: 1420.97; MS (m/z): 1421.75 (M+1)+, 1443.72 (M+Na)+; TLC: Rf: 0.40 (ethyl acetate/methanol=10/1); HPLC RT: 13.58 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 155
[α-Carboxy-Sar]-3-[NMeIle]-4-cyclosporin




To a solution of LDA (2.0 M in tetrahydrofuran, 5 ml, 10 mmol) in tetrahydrofuran (15 ml) at −78° C. under nitrogen atmosphere was added [N-MeIle]-4-cyclosporin (1.20 g, 1.00 mmol) in tetrahydrofuran (15 ml) over 3 min After the mixture was stirred at −78° C. for 3 hours, carbon dioxide gas was bubbled into the reaction mixture for 1 hour. Then the mixture was allowed to warm to room temperature slowly and kept stirring for another 3 hours. Most of tetrahydrofuran was evaporated under reduced pressure. Dichloromethane (100 ml) and water (50 ml) were added. The PH of the mixture was adjusted to around 5 by adding aqueous citric acid solution. The mixture was then separated and the organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1.10 g of crude product, which was used for next step without purification [Molecular Formula: C63H111N11O14; Exact Mass: 1245.83; MS (m/z): 1246.68 (M+1)+].
Example 156
[α-Methoxycarbonyl-Sar]-3-[NMeIle]-4-cyclosporin




To a mixture of [α-carboxy-Sar]-3-[N-MeIle]-4-cyclosporin (1.00 g, 0.80 mmol) and potassium carbonate (0.70 g, 5.07 mmol) in N,N-dimethylformamide (10 ml) was added iodomethane (1.50 g, 10.56 mmol). The mixture was stirred overnight at room temperature. Dichloromethane (80 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and evaporated under reduced pressure to give crude 1.00 g of product [Molecular Formula: C64H113N11O14; Exact Mass: 1259.85; MS (m/z): 1260.51 (M+1)+].
Example 157
[(R)-α-Hydroxymethyl-Sar]-3-[N-MeIle]-4-cyclosporin




To a suspension of [α-methoxycarbonyl-Sar]-3-[N-MeIle]-4-cyclosporin (1.00 g, 0.79 mmol) and lithium chloride (0.60 g, 14.11 mmol) in methanol (80 ml) was added sodium borohydride (3.00 g, 79.26 mmol) in portions. The mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give 420 mg of product [Molecular Formula: C63H113N11O13; Exact Mass: 1231.85; MS (m/z): 1232.59 (M+1)+; TLC Rf: 0.32 (dichloromethane/methanol=95/5); HPLC RT: 14.32 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 158
[α-Methylene-Sar]-3-[NMeIle]-4-cyclosporin




[α-Methylene-Sar]-3-[N-MeIle]-4-cyclosporin was prepared according to the method described in Example 28 [Molecular Formula: C63H111N11O12; Exact Mass: 1213.84; MS (m/z): 1214.59 (M+1)+; TLC Rf: 0.34 (hexane/acetone=6/1); HPLC RT: 17.47 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid), operation temperature: 64° C.; detector: 210 nm].
Example 159
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[NMeIle]-4-cyclosporin




To a solution of [α-Methylene-Sar]-3-[N-MeIle]-4-cyclosporin (300 mg, 0.25 mmol) and 2-diethylaminoethanethiol hydrochloride (408 mg, 2.41 mmol) in methanol (20 ml) was added lithium hydroxide (116 mg, 4.83 mmol). The reaction mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (30 ml) were added and the mixture was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 170 mg of product [Molecular Formula: C69H126N12O12S; Exact Mass: 1346.93; MS (m/z): 1347.68 (M+1)+; TLC Rf: 0.32 (dichloromethane/methanol=95/5); HPLC RT: 13.54 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 160
[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[NMeIle]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[N-MeIle]-4-cyclosporin (0.39 g, 0.32 mmol) in benzene (20 ml) were added a solution of sodium hydroxide (0.80 g, 20 mmol) in water (1 ml), 2-bromo-N,N-diethylethylamine hydrobromide (2.40 g, 9.20 mmol) and tetra-n-butylammonium bromide (0.10 g, 3.10 mmol). The mixture was stirred at 30° C. for 40 hours. Ice water (10 ml) was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give 270 mg of product [Molecular Formula: C69H126N12O13; Exact Mass: 1330.96; MS (m/z): 1331.73 (M+1)+; TLC Rf: 0.34 (dichloromethane/methanol=95/5); HPLC RT: 13.42 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 161
[α-Methylene-Sar]-3-[NMeVal]-4-cyclosporin




[α-Methylene]-3-[N-MeVal]-4-cyclosporin was prepared according to the method described in Example 28. The product was purified by chromatography on silica gel (ethyl acetate/methanol). [Molecular Formula: C62H109N11O12; Exact Mass: 1199.83; MS (m/z): 1200.56 (M+1)+, 1222.72 (M+Na)+].
Example 162
[(S)-(2-(N,N-dimethylamino)ethylthio)methyl-Sar]-3-[NMeVal]-4-cyclosporin




[α-Methylene-Sar]-3-[N-MeVal]-4-cyclosporin (88 mg, 0.07 mmol) and 2-(N,N-dimethyl)ethanethiol hydrochloride (0.10 g, 7.30 mmol) were dissolved in methanol (20 ml), followed by adding 20 equivalents of lithium hydroxide. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 30 mg of pure product [Molecular Formula: C66H120N12O12S; Exact Mass: 1304.89; MS (m/z): 1305.68 (M+1)+, 1327.83 (M+Na)+; TLC Rf: 0.05 (ethyl acetate/methanol=5/1); HPLC RT: 12.23 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 163
[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[NMeVal]-4-cyclosporin




[α-Methylene-Sar]-3-[N-MeVal]-4-cyclosporin (0.20 g, 0.16 mmol) and 2-(N,N-9diethyl)ethanethiol hydrochloride (0.28 g, 1.70 mmol) were dissolved in methanol (20 ml), followed by adding 20 equivalents of lithium hydroxide (77 mg, 3.20 mmol). The mixture was stirred overnight. After removal of solvent, the residue was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give 100 mg of pure product [Molecular Formula: C68H124N12O12S; Exact Mass: 1332.92; MS (m/e): 1333.58 (M+1)+, 1355.79 (M+Na)+; TLC Rf: 0.08 (ethyl acetate/methanol=5/1); HPLC RT: 12.77 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 164
[(R)-α-Hydroxymethyl-Sar]-3-[NMeVal]-4-cyclosporin




[(R)-α-Hydroxymethyl-Sar]-3-[N-MeVal]-4-cyclosporin was prepared according to the method described in Example 2. The product was purified by chromatography on silica gel (ethyl acetate/methanol) [Molecular Formula: C62H111N11O13; Exact Mass: 1217.84; MS (m/z): 1218.56 (M+1)+, 1240.75 (M+Na)+].
Example 165
[(R)-(2-(N,N-dimethylamino)ethoxy)methyl-Sar]-3-[NMeVal]-4-cyclosporin




To a solution of [(R)-α-hydroxymethyl-Sar]-3-[N-MeVal]-4-cyclosporin (0.12 g, 0.10 mmol) in benzene (15 ml) were added sodium hydroxide (0.20 g. 5.00 mmol), tetramethylammonium hydroxide pentahydrate (0.18 g, 1.00 mmol) and 3-dimethylaminoethyl chloride hydrochloride (0.14 g, 1.00 mmol). The mixture was stirred at 30° C. overnight. Ice water (20 ml) was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel (dichloromethane/methanol=95/5) to give the 30 mg of pure product [Molecular Formula: C66H120N12O13; Exact Mass: 1288.91; MS (m/z): 1289.73 (M+1)+, 1311.71 (M+Na)+; TLC Rf: 0.14 (dichloromethane/methanol=10/1); HPLC RT: 12.00 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 166
[(R)—(N-Piperidinyl)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




[α-Methylene-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (0.37 g, 0.30 mmol) and piperidine (0.26 g, 3.00 mmol) were dissolved in acetonitrile/water (20 ml) in the presence of the catalytic amount of copper (II) acetate. The mixture was stirred overnight at room temperature. After removal of solvent, the residue was dissolved in dichloromethane (30 ml). The dichloromethane phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was further purified by chromatography on silica gel (dichloromethane/methanol, 96/4) to give 0.17 g of product [Molecular Formula: C68H122N12O13; Exact Mass: 1314.93; MS (m/z): 1315.74 (M+1)+, 1337.86 (M+Na)+; TLC Rf: 0.10 (ethyl acetate/methanol=5/1); HPLC RT: 11.70 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% TFA); operation temperature: 64° C.; detector: 210 nm)].
Example 167
[(γ-Allyloxy)-NMeLeu]-4-cyclosporin




Under nitrogen atmosphere, to a mixture of [(γ-Hydroxy)-NMeLeu]-4-cyclosporin (FW 1218.61, 800 mg, 0.66 mmol) and ally 2,2,2-trichloroacetimidate (FW 202.47, 930 mg, 4.6 mmol) in 150 ml of DCM was added trimethylsilyl trifluoromethanesulfonate (FW 222.26, d 1.228, 250 mg, 1.12 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for overnight. Then the mixture was washed with saturated NaHCO3 water solution and brine. The organic layer was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by column chromatography using DCM/MeOH (98/2) to give product [Molecular formula: C65H115N11O13; Exact Mass: 1257.87; MS (m/z): 1280.7 (M+Na)+; TLC Rf: 0.46 (DCM/MeOH=95/5); HPLC RT: 16.45 minutes (C8 reverse phase column, 250 mm, acetonitrile/0.05% TFA in water, operation temperature: 64° C.; Detector: 210 nm)].
Example 168
[(R)-2-Nitroethyl-Sar]-3-cyclosporin




To a solution of [α-methylene-Sar]-3-cyclosporin (FW 1214.62, 1.0 g, 0.82 mmol) in nitromethane (15 ml) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (FW 152.24, 1.0 g, 6.6 mmol). After stirred at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. The residue was mixed with water dichloromethane. The dichloromethane layer was washed with aqueous citric acid solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (hexane/acetone=3/1) to give the product [Molecular formula: C64H114N12O14; Exact Mass: 1274.86; MS (m/z): 1275.54 (M+1)+].
Example 169
[(R)-2-Aminoethyl-Sar]-3-cyclosporin




To a mixture of [(R)-2-nitroethyl-Sar]-3-cyclosporin (FW 1275.66, 210 mg, 0.16 mmol) and zinc (FW 65.38, 1 g, 15.3 mmol) in ethanol (20 ml) was added 10% aqueous hydrochloric acid (10 ml). The reaction mixture was stirred at room temperature overnight (monitored by LC-MS) and filtered. The filter cake was washed with ethanol. The filtrate was concentrated and diluted with dichloromethane. The dichloromethane layer was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C64H116N12O12; Exact Mass: 1244.88; MS (m/z): 1245.54 (M+1)+].
Example 170
[(R)-2-(N,N-Dimethylamino)ethyl-Sar]-3-Cyclosporin




To a solution of [(R)-2-aminoethyl-Sar]-3-Cyclosporin (FW 1245.68, 122 mg, 0.1 mmol) in chloroform (6 ml) were added formaldehyde aqueous 37% solution (0.6 ml) and acetic acid (6 drops). The reaction mixture was stirred at room temperature for 5 min. Then tetramethylammonium triacetoxyborohydride (FW 263.10, 131 mg, 0.5 mmol) was added and the reaction mixture was continued to stir for one hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give the product [Molecular formula: C66H120N12O12; Exact Mass: 1272.91; MS (m/z): 1273.70 (M+1)+; TLC Rf: 0.27 (dichloromethane/methanol); HPLC RT: 12.42 minutes].
Example 171
[(R)-2-(N,N-Diethylamino)ethyl-Sar]-3-Cyclosporin




To a solution of 3-amino cyclosporine (FW 1245.68, 124 mg, 0.1 mmol) in chloroform (6 ml) were added acetaldehyde (FW 44.06, 78 mg, 1.77 mmol) and acetic acid (drops). The reaction mixture was stirred at room temperature for 5 min. Then tetramethylammonium triacetoxyborohydride (FW 263.10, 126 mg, 0.48 mmol) was added and the reaction mixture was continued to stir for 1 hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give product [Molecular formula: C68H124N12O12; Exact Mass: 1300.95; MS (m/z): 1301.72 (M+1)+; TLC Rf: 0.33 (dichloromethane/methanol=95/5); HPLC RT: 13.28 minutes (C8 reverse phase column, 250 mm, acetonitril-water/(0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 172
[(2-Methoxy-2-oxoethyl)-Sar]-3-cyclosporin




n-Butyllithium (15.84 ml, 2.89 M, 45.79 mmol) was added to a solution of diisopropylamine (6.50 ml, 45.79 mmol) in tetrahydrofuran (80 ml) at −78° C. under nitrogen and the reaction mixture was stirred for an hour. A solution of cyclosporine A (5.00 g, 4.16 mmol) in tetrahydrofuran (20 ml) was added over 10 minutes and the mixture was stirred at −78° C. for another two hours. Then methyl bromoacetate (7.00 g, 45.79 mmol) and the reaction mixture was stirred at −78° C. for one hour. The reaction mixture was allowed to warm up to room temperature slowly and stirred overnight. Most of tetrahydrofuran was removed under vacuum at room temperature. Ethyl acetate (50 ml) and 50 ml brine were added and separated. The aqueous layer was extracted with ethyl acetate (20 ml×3). The combined ethyl acetate layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column to give to give 2.11 g of [(2-methoxy-2-oxoethyl)-Sar]-3-cyclosporin [Molecular Formula: C65H115N11O14; Exact Mass: 1273.86; MS (m/z): 1274.44 (M+1)+, 1296.63 (M+Na)+].
[(2-(t-Butoxy)-2-oxoethyl)-Sar]-3-cyclosporin was synthesized using a method analogous to a procedure described by Seebach D, et al., 1993, Helv Chim Acta, 76, 1564-1590.
Example 173
[(R)-(2-Hydroxyethyl)-Sar]-3-cyclosporin and [(S)-(2-hydroxyethyl)-Sar]-3-cyclosporin







[(2-Methoxy-2-oxoethyl)-Sar]-3-cyclosporin (1.00 g, 0.79 mmol) was dissolved in tetrahydrofuran (30 ml), followed by adding cesium chloride (1.00 g, 5.94 mmol) and sodium borohydride (1.00 g, 26.43 mmol). Then 30 ml of methanol was added dropwise to the mixture over one hour. After addition, the mixture was stirred at room temperature for another hour. Most solvent was then evaporated under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give the product of isomer A as [(R)-(2-hydroxyethyl)-Sar]-3-cyclosporin [Molecular Formula: C64H115N11O13; Exact Mass: 1245.87; MS (m/z): 1246.49.52 (M+1)+, 1268.72 (M+Na)+; TLC Rf: 0.46 (dichloromethane/methanol=9:1); HPLC RT: 16.06 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)] and the product of isomer B as [(S)-(2-hydroxyethyl)-Sar]-3-cyclosporin [Molecular Formula: C64H115N11O13; Exact Mass: 1245.87; MS (m/z): 1246.49 (M+1)+, 1268.68 (M+Na)+; TLC Rf: 0.46 (dichloromethane/methanol=9:1); HPLC RT: 15.15 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64° C.; detector: 210 nm)].
Example 174
[(R)-2-Nitroethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-Cyclosporin




To a solution of [α-Methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (FW 1230.62, 1.6 g, 1.3 mmol) in 20 ml of nitromethane was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was mixed with water and dichloromethane and separated. The organic layer was washed with aqueous citric acid solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give the product (R-isomer) 600 mg [Molecular formula: C64H114N12O15; Exact Mass: 1290.85; MS (m/z): 1291.72 (M+1)+. HPLC RT: 14.95 minutes]. (S-isomer) 360 mg [Molecular formula: C64H114N12O15; Exact Mass: 1290.85; MS (m/z): 1291.72 (M+1)+; HPLC RT: 14.43 minutes].
Example 175
[(R)-2-Aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-Cyclosporin




To a mixture of [(R)-2-nitroethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1291.66, 400 mg, 0.31 mmol) and zinc (1.5 g) in ethanol (30 ml) was added 10% aqueous hydrochloric acid (30 ml). The reaction mixture was stirred at room temperature overnight (monitored by LC-MS) and filtered. The filter cake was washed with ethanol. The combined filtrate was concentrated and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C64H116N12O13; Exact Mass: 1260.88; MS (m/z): 1261.70 (M+1)+].
Example 176
[(R)-2-(N,N-Dimethylamino)ethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a solution of [(R)-2-aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1261.68, 180 mg, 0.14 mmol) in chloroform (6 ml) were added formaldehyde aqueous 37% solution (0.8 ml) and acetic acid (8 drops). The reaction mixture was stirred at room temperature for 5 min. Then tetramethylammonium triacetoxyborohydride (263.10, 200 mg, 0.76 mmol) was added and the reaction mixture was continued to stir for one hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C66H120N12O13; Exact Mass: 1288.91; MS (m/z): 1289.76 (M+1)+; TLC Rf: 0.32 (dichloromethane/methanol=9/1); HPLC RT: 11.14 minutes].
Example 177
[(R)-2-(N,N-Diethylamino)ethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-Cyclosporin




To a solution of [(R)-2-aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1261.68, 129 mg, 0.10 mmol) in chloroform (10 ml) were added acetaldehyde (FW 44.06, 80 mg, 1.8 mmol) and acetic acid (7 drops). The reaction mixture was stirred at room temperature for 5 min. Then tetramethylammonium triacetoxyborohydride (FW 263.10, 200 mg, 0.76 mmol) was added and the reaction mixture was continued to stir for one hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C68H124N12O13; Exact Mass: 1316.94; MS (m/z): 1317.70 (M+1)+; TLC Rf: 0.39 (Dichloromethane/methanol=9/1); HPLC RT: 12.06 minutes].
Example 178
[(S)-2-Aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin




To a mixture of [(S)-2-nitroethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1291.66, 350 mg, 0.27 mmol) and zinc (1.5 g) in ethanol (25 ml) was added 10% aqueous hydrochloric acid (15 ml). The reaction mixture was stirred at room temperature overnight (monitored by LC-MS) and filtered. The filter cake was washed with ethanol. The combined filtrate was concentrated and diluted with dichloromethane. The organic solution was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=96/4) to give the product [Molecular formula: C64H116N12O13; Exact Mass: 1260.88; MS (m/z): 1261.64 (M+1)+].
Example 179
[(S)-2-(N,N-Dimethylamino)ethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-Cyclosporin




To a solution of [(S)-2-aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1261.68, 13 0 mg, 0.10 mmol) in chloroform (10 ml) were added formaldehyde aqueous 37% solution (0.7 ml) and acetic acid (7 drops). The reaction mixture was stirred at room temperature for 5 min. Then tetramethylammonium triacetoxyborohydride (263.10, 200 mg, 0.76 mmol) was added and the reaction mixture was continued to stir for one hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over Magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C66H120N12O13; Exact Mass: 1288.91; MS (m/z): 1289.70 (M+1)+; TLC Rf: 0.35 (Dichloromethane/methanol=9/1); HPLC RT: 11.02 minutes].
Example 180
[(S)-2-(N,N-Diethylamino)ethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-Cyclosporin




To a solution of [(S)-2-aminoethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin (FW 1261.68, 129 mg, 0.10 mmol) in chloroform (10 ml) were added acetaldehyde (FW 44.06, 80 mg, 1.8 mmol) and acetic acid (7 drops). The reaction mixture was stirred at room temperature for 5 minutes. Then tetramethylammonium triacetoxyborohydride (FW 263.10, 200 mg, 0.76 mmol) was added and the reaction mixture was continued to stir for one hour. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=95/5) to give the product [Molecular formula: C68H124N12O13; Exact Mass: 1316.94; MS (m/z): 1317.70 (M+1)+; TLC Rf: 0.41 (Dichloromethane/methanol=9/1); HPLC RT: 11.96 minutes].
Example 181
[(R)-2-Nitro-3-(N,N-Dimethylamino)propyl-Sar]-3-Cyclosporin




To a mixture of [(R)-2-nitroethyl-Sar]-3-cyclosporin (FW 1275.66, 360 mg, 0.28 mmol) and dimethymethyleneammonium iodide (FW 185.01, 550 mg, 15.4 mmol) acetonitrile (in 25 ml) was added triethylamine (10 drops). The reaction mixture was stirred at room temperature overnight (monitored by LC-MS). The mixture was concentrated and diluted with dichloromethane. The organic layer was washed with aqueous water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used for next step.
Example 182
[(R)-3-(N,N-Dimethylamino)propyl-Sar]-3-Cyclosporin




To a mixture of cylcosporine (crude form previous step FW 1332.76, 0.28 mmol) and tri-n-butyltin hydride (FW 291.07, 0.41 g, 1.4 mmol) in benzene (25 ml) was added AIBN (FW 164.21, 46 mg, 0.28 mmol) under nitrogen atmosphere. The mixture was heated to reflux with stirring for 8 hours. After the reaction was completed (monitored by LC-MS), the reaction mixture was washed with aqueous saturated sodium bicarbonate solution and brine followed by evaporated under vacuum. The residue was purified by chromatography (Dichloromethane/methanol=95/5) to give the product [Molecular formula: C67H122N12O12; Exact Mass: 1286.93; MS (m/z): 1287.71 (M+1)+; TLC Rf: 0.36 (dichloromethane/methanol=95/5); HPLC RT: 12.57 minutes].
Example 183
[(R)-3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a solution of [α-methylene-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (0.61 g, 0.50 mmol) and diethyl malonate (1.00 g, 6.25 mmol) in ethanol anhydrous (30 ml) was added sodium ethoxide (0.82 g, 12.05 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was mixed with water (30 ml) and dichloromethane (80 ml) and separated. The organic layer was washed with aqueous citric acid and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (hexane/acetone=2/1) to give the product. [Molecular formula: C70H123N11O17; Exact Mass: 1389.91; MS (m/z): 1390.56 (M+1)+; TLC Rf: 0.30 (dichloromethane/methanol=95/5); HPLC RT: 15.32 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% TFA); operation temperature: 64° C.; Detector: 210 nm)].
Example 184
[(R)-3-Hydroxy-2-(hydroxylmethyl)propyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin




To a suspension [(R)-3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin (150 mg, 0.11 mmol) and lithium chloride (580 mg, 13.81 mmol) in methanol (50 ml) was added sodium borohydride (1.20 g, 31.75 mmol) in portions. The mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (100 ml) and water (50 ml) were added and separated. The dichloromethane layer was washed with brine, dried over Magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol=97/3) to give product. [Molecular formula: C66H119N11O15; Exact Mass: 1305.89; MS (m/z): 1306.48 (M+1)+; TLC Rf: 0.22 (dichloromethane/methanol=9/1); HPLC RT: 10.65 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% TFA); operation temperature: 64° C.; Detector: 210 nm)].
Reference Example 1
[α-Carboxy-Sar]-3-cyclosporin




n-Butyllithium (2.87 M, 27 mmol, 9.4 ml, 10 eq) was added to a solution of diisopropylamine (3.8 ml, 27 mmol, 10 eq) in tetrahydrofuran (80 ml) at −78° C. under nitrogen. After the reaction mixture was stirred for an hour, a solution of cyclosporine A (3.2 g, 2.66 mmol) in tetrahydrofuran (15 ml) was added over 10 min. The stirring was continued at −78° C. for 2 hours. Carbon dioxide gas was bubbled through the reaction mixture for 20-25 minutes and stirred at −78° C. for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to 0° C. slowly. Most of tetrahydrofuran was removed under vacuum at room temperature. The residue was quenched by the addition of saturated citric acid solution and the pH of the mixture was adjusted to around 7-8. The unreacted cyclosporin was extracted with ether (40 ml×2). The PH of the aqueous layer was adjusted to 3 ̃4 with 1 N hydrochloric acid and the precipitated oil was extracted with ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml×3). The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give semi-solid product (2.61 g, yield: 78%) [Molecular Formula: C63H111N11O14; Exact Mass: 1245.83; MS (m/z): 1246.7 (M+1)+, 1268.7 (M+Na)+].
[α-Carboxy-Sar]-3-cyclosporin was synthesized according to a procedure described by Seebach D, et al., 1993, Helv Chim Acta, 76, 1564-1590.
Reference Example 2
[α-Methylene-Sar]-3-cyclosporin




[α-Methylene-Sar]-3-cyclosporin can also be prepared using a method analogous to the procedure described in WO2012/051194A1.
Reference Example 3
Synthesis of [N-MeVal]-4-cyclosporin (SDZ-220-384)
[N-MeVal]-4-Cyclosporin (SDZ 220-384) was prepared according to procedures described by Papageorgiou C, et al., 1994, Bioorg & Med Chem Lett, 4, 267-272 and its key cyclosporine ring-opening between position 3 and 4 cited as reference 14: Su Z and Wenger R, Unpublished results; Papageorgiou C, et al., 1994, J. Med. Chem., 37, 3674-3676 and its key cyclosporine ring-opening between position 3 and 4 cited as reference 11: Su Z and Wenger R, Unpublished results.
Cyclosporin A-acetate




To a solution of cyclosporin A (1) (12.00 g, 19.98 mmol) in acetic anhydride (MW: 102.09, d 1.082, 40 ml) were added pyridine (MW: 79.01, d 0.978, 40 ml) and 4-N,N-dimethylaminopyridine (MW: 122.17, 0.40 g). This mixture was stirred for overnight at room temperature, and then the mixture was diluted with 600 ml of ethyl acetate. The mixture was washed with brine, saturated ammonium chloride solution and 15% of sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and evaporated under the reduced pressure. Then all of pyridine was azeotropically evaporated out under the reduced pressure by adding toluene to the mixture to give a pale yellow solid residue, which was purified by flash chromatography on a silica gel column (100-200 mesh) with eluent of ethyl acetate/hexane (1/3) to give the 11.80 g (9.48 mmol, 95%) of cyclosporin A-acetate (2).
MeLeuValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-Ome




To a suspension of trimethyloxonium-fluoroborate (MW: 147.91, 2.96 g, 20 mmol, 2.50 equiv.) in dichloromethane (80 ml) was added cyclosporine A-acetate (2) (10.00 g, 8.00 mmol). The suspension was stirred for 18 hours at room temperature, and then a solution of sodium methoxide (9.90 mmol) in methanol (40 ml) was added. After the mixture was stirred for another half hour, 2 N solution of sulfuric acid in methanol (40 ml) was added. The mixture was stirred for 15-30 minutes at room temperature and neutralized with 15% potassium bicarbonate solution. Then the mixture was extracted twice with 700 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography on a silica column (100-200 mesh) with eluent of methanol/methyl t-butyl ether to give the 7.15 g (5.60 mmol, 70%) of linear undecapeptide peptide (1).
Phenylthiourea-MeLeuValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-Ome




To a solution of linear undecapeptide peptide (3) (7.00 g, 5.50 mmol) in tetrahydrofuran (80 ml) was added phenyl isothiocyanate (MW: 135.19, d 1.130, 0.86 ml, 7.15 mmol, 1.30 equiv.). The mixture was stirred for 3 hours at room temperature and evaporated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (100-200 mesh) with eluent of acetone in hexane (1/5) to give the 6.99 g (4.95 mmol, 90%) of linear phenylthiourea undecapeptide (4) [Exact Mass: 1410.89; MS m/z: 1433.88 (M+Na)+].
ValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-Ome




To a solution of linear phenylthiourea undecapeptide (4) (6.80 g, 4.82 mmol) in toluene (300 ml) was added trifluoroacetic acid (MW: 114.02, d 1.480, 8.00 ml) at room temperature. The mixture was stirred for 1.5 to 2 hours and quenched by a slurry of sodium bicarbonate in water. Then the mixture was separated and the water phase was extracted with toluene (100 ml) and ethyl acetate (100 ml) subsequently. The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography on a silica column (100-200 mesh) with eluent of acetone/hexane (3/1) to give the 3.88 g (3.37 mmol, 70%) of linear decapeptide peptide (5) [Exact Mass: 1148.78; MS m/z: 1149.78 (M+1)+].
This Edman degradation was carried according to the similar method described by Edman P, et al, 1967, Eur. J. Biochem., 1, 80.
BocMeValValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-Ome




To a solution of linear decapeptide peptide (5) (3.80 g, 3.30 mmol) in dichloromethane (150 ml) were added Boc-MeVal (6) (MW: 231.29, 0.92 g, 3.96 mmol, 1.2 equiv.), 1-propanephosphonic acid cyclic anhydride (MW: 318.18, 2.10 ml, 50 wt. % solution in ethyl acetate) and triethylamine (MW: 101.19, d 0.726, 0.46 ml, 3.30 mmol) at 0° C. The resulting mixture was stirred at room temperature for 5 hours. Then the mixture was washed with brine. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over sodium sulphate. Removal of the solvent under reduced pressure gave the residue, which was purified by flash chromatography on a silica column (100-200 mesh) with eluent of acetone/hexane (1/2.5) to give the 4.05 g (2.97 mmol, 90%) of linear Boc-N-MeVal-decapeptide peptide (7) [Exact Mass: 1361.91; MS m/z: 1384.91 (M+Na)+].
BocMeValValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-OH




To a solution of linear [Boc-N-MeVal]-4-decapeptide peptide (7) (4.00 g, 2.94 mmol) in ethyl alcohol (150 ml) at 0° C. was added 0.5 N sodium hydroxide solution (7.1 ml, 1.20 equiv.). The mixture was stirred and kept at 0° C. for 16 hours. Then the PH of the mixture was adjusted to around 3 by adding 0.5 N hydrochloric acid. Most of solvent was evaporated under the reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The mixture was washed with a pH 3 buffer, dried over sodium sulphate, filtered and evaporated under the reduced pressure. The residue was purified by flash chromatography on a silica column (100-200 mesh) with eluent of methanol/ethyl acetate (1/8) to yield 2.55 g (1.89 mmol, 64.3%) of the free acid (8).
MeValValMeLeuAlaDAlaMeLeuMeLeuMeValMeBmt(OAc)AbuSar-OH




To a solution of free acid (8) (2.55 g, 1.89 mmol) in dichloromethane (25 ml) was slowly added 5 ml of trifluoroacetic acid (MW: 114.02, d 1.480) at 0° C. The solution was stirred at room for 2 hours. Then ethyl acetate (300 ml) was added and the solvent was removed under reduced pressure. Another ethyl acetate (300 ml) was added and the solvent was removed under reduced pressure again. The residue was purified by flash chromatography on a silica gel column (100-200 mesh) with eluent of methanol/acetone (1/3) to give the 2.01 g (1.61 mmol, 85%) of linear [N-MeVal]-4-decapeptide peptide free acid (9) [Exact Mass: 1247.85; MS m/z: 1248.85 (M+1)+].
[N-MeVal]-4-Cyclosporin acetate




To a solution of linear [N-MeVal]-4-decapeptide peptide free acid (9) (1.03 g, 0.83 mmol) in dichloromethane (250 ml) were added 1-propanephosphonic acid cyclic anhydride (MW: 318.18, 0.53 ml, 50 wt. % solution in ethyl acetate), 2,4,6-collidine (MW: 121.18, d 0.917, 0.11 ml, 0.83 mmol)) at 0° C. The mixture was stirred at room temperature for 24 hours. Then the mixture was passed through a thin layer of silica gel and washed twice by 40 ml of ethyl acetate. The collected organic solution was evaporated under the reduced pressure. The residue was purified by flash chromatography on a silica gel column (230-400 mesh) with eluent of methanol/acetone (1/6) to give the 611 mg (0.50 mmol, 60%) of (N-Methyl-Val)-4-Cyclosporin acetate (10) [Exact Mass: 1229.84; MS m/z: 1252.82 (M+Na)+].
[N-MeVal]-4-Cyclosporin




To a solution of [N-MeVal]-4-Cyclosporin acetate (10) (0.60 g, 0.49 mmol) in methanol (40 ml) was added a solution of sodium methoxide in methanol (0.5 M, 1.9 ml, 2.0 equiv.). The mixture was stirred for 0.5 hour at 0° C. and 24 hours at room temperature. The PH of the mixture was adjusted to around 6 by adding 0.5 N hydrochloric acid. After the solvent was evaporated under reduced pressure, the residue was dissolved in 200 ml of ethyl acetate. The organic solution was washed by aqueous sodium bicarbonate and brine, dried over sodium sulphate and filtered. After removal of solvent, the residue was purified by flash chromatography on a silica gel column (230-400 mesh) with eluent of acetone/hexane (1/2) to give the 406 mg (0.34 mmol, 70%) of [N-MeVal]-4-Cyclosporin (11) [Exact Mass: 1187.83; 84; MS m/z: 1210.81 (M+Na].
Reference Example 4
[N-MeIle]-4-Cyclosporin (NIM-811) was prepared according to the procedure used for the synthesis of (N-MeVal)-4-cyclosporin (SDZ 220-384).
Reference Example 5
[N-MeThr]-4-Cyclosporin can be prepared according to the procedure used for the synthesis of (N-MeVal)-4-cyclosporin (SDZ 220-384).
Reference Example 6
The side chain intermediates were synthesized according to procedures described by Urquhart G G, 1994, Org Synth, Coll. Vol III, 363
2-Morpholinoethanethiol




A mixture of 4-(2-chloroethyl)morpholine (7.00 g, 37 mmol) and thiourea (2.90 g, 38 mmol) in 95% ethanol (55 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (3.40 g, 85 mmol) in water (20 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The benzene layer was washed with brine, dried over magnesium sulfate and evaporated to provide 3.80 g of crude product, which was used for the addition reaction.
2-(N-Piperidinyl)ethanethiol




The mixture of 1-(2-chloroethyl)piperidine hydrochloride (7.00 g, 38 mmol) and thiourea (4.60 g, 61 mmol) in 95% ethanol (30 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (2.40 g) in water (20 ml) was added. The mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with ether. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3.20 g of crude product, which was used for the addition reaction without purification.
2-(N-Pyrrolidinyl)ethanethiol




The mixture of 1-(2-chloroethyl)piperidine hydrochloride (7.0 g, 41 mmol) and thiourea (3.20 g, 40 mmol) in 95% ethanol (30 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (3.40 g, 85 mmol) in water (20 ml) was added. The mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3.80 g of crude product, which was used for the addition reaction without purification.
3-(N-Pyrrolidinyl)propanethiol




To a suspension of 1-bromoro-3-chloropropane (30.00 g, 191 mmol) and potassium carbonate (17.00 g, 123 mmol) in dichloromethane (160 ml) was added pyrrolidine (3.50 g, 49 mmol) portions. The mixture was stirred at room temperature overnight. Then the mixture was filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=95/5) to give 6.00 g of product.
A mixture of 1-(3-chloropropyl)pyrrolidine (3.4 g, 23 mmol) and thiourea (1.8 g, 23 mmol) in 95% ethanol (55 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (1.20 g, 30 mmol) in water (10 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1.80 g of crude product, which was used for the addition reaction.
3-(N-Piperidinyl)propanethiol




The mixture of 1-(3-chloropropyl)piperidine hydrochloride (7.50 g, 38 mmol) and thiourea (4.60 g, 61 mmol) in 95% ethanol (30 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (2.40 g) in water (20 ml) was added. The mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with ether. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3.50 g of crude product, which was used for the addition reaction without purification.
3-Morpholinopropanethiol




To a suspension of 1-bromoro-3-chloropropane (30.00 g, 191 mmol) and potassium carbonate (14.00 g, 101 mmol) in dichloromethane (160 ml) was added morpholine (4.00 g, 46 mmol) in portions. Then the mixture was stirred at room temperature overnight. The mixture was filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate) to give 5.60 g of product.
A mixture of 1-(3-chloropropyl)morpholine (4.20 g, 25.76 mmol) and thiourea (2.00 g, 26.27 mmol) in 95% ethanol (55 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (1.3 g, 32.50 mmol) in water (10 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The benzene layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2.20 g of crude product, which was used for the addition reaction.
2-(4-Methyl-N-piperazinyl)ethanethiol




A mixture of 2-(4-methylpiperazino)ethyl chloride (8.00 g, 40 mmol) and thiourea (4.87 g, 64 mmol) in 95% ethanol (55 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (2.60 g) in water (20 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The benzene layer was washed with brine, dried magnesium sulfate and evaporated to provide 3.0 g of crude product, which was used for the addition reaction.
3-(4-Methyl-N-piperazinyl)propanethiol




A mixture of 3-(4-methylpiperazino)propyl chloride (8.5 g, 40 mmol) and thiourea (4.87 g, 64 mmol) in 95% ethanol (70 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (2.6 g) in water (20 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with ether. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to provide 2.5 g of crude product, which was used for the addition reaction.
3-(N-Ethyl-N-isopropylamino)propanethiol




To a suspension of 1-bromoro-3-chloropropane (11.00 g, 70 mmol) and potassium carbonate (13.00 g, 94 mmol) in dichloromethane (100 ml) was added ethylisopropylamine (4.10 g, 47 mmol) in portions. The mixture was stirred at room temperature overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate/methanol=95/5) to give 6.10 g of product.
A mixture of 3-chloropropylethylisopropylamine (4.20 g, 25.66 mmol) and thiourea (2.00 g, 26.32 mmol) in 95% ethanol (55 ml) was heated to reflux for 24 hours. A solution of sodium hydroxide (1.30 g, 32.50 mmol) in water (10 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with benzene. The benzene layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1.20 g of crude product, which was used for the addition reaction.
3-Aminopropanethiol




A mixture of N-(3-bromopropyl)phthalimide (20.00 g, 74.63 mmol) and thiourea (9.98 g, 131.34 mmol) in 95% ethanol (80 ml) was heated to reflux for 3 hours. A solution of sodium hydroxide (4.48 g, 111.94 mmol) in water (30 ml) was added, and the mixture was continued to reflux for another 3 hours. After cooled to room temperature, the mixture was evaporated under reduced pressure. The residue was mixed with ethyl acetate (50 ml) and brine (50 ml). The organic layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was mixed with toluene (100 ml) and heated to reflux with removal of water azeotropically for two hours. After removal of toluene, the residue was purified by chromatography on silica gel with hexane and ethyl acetate as solvent to give 9.10 g of N-(3-mercaptopropyl)phthalimide. To a solution of N-(3-mercaptopropyl)phthalimide in methanol (50 ml) was added ethanolamine. The mixture was stirred and heated to reflux for two hours. After cooled to room temperature, the mixture was used for the addition reaction without further purification.
2-Mercaptoethylpiperazine




To a suspension of piperizaine (30.00 g, 348.27 mmol) and sodium carbonate (106 g, 348.27 mmol) in dichloromethane (200 ml) was added dropwise a solution of Di-tert-butyl dicarbonate (18.98 g, 87.07 mmol) in dichloromethane (30 ml) at room temperature for one hour. Then the mixture was stirred at room temperature overnight. The mixture was mixed with water (100 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in dichloromethane (150 ml). Sodium carbonate (15.55 g, 146.77 mmol) and 1-bromo-2-chloroethane (21.05 g, 146.77 mmol) were added. The mixture was stirred at room temperature for a weekend. The mixture was mixed with water (100 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using hexane and ethyl acetate as eluent to give 6.85 g of 1-Boc-4-(2-chloroethyl)piperazine.
To a solution of 1-Boc-4-(2-chloroethyl)piperazine (6.85 g, 27.62 mmol) in methanol (50 ml) was added thiourea (4.12 g, 55.24 mmol). The mixture was heated to reflux for 2 hours. A solution of sodium hydroxide (1.66 g, 41.43 mmol) in water (10 ml) was added, and the mixture was continued to reflux for another hour. Then most solvent was evaporated under reduced pressure. The residue was mixed with ethyl acetate (50 ml) and brine (30 ml) and separated. The ethyl acetate was dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (20 ml). 4 M hydrochloric acid in dioxane (10 ml) was added. The mixture was stirred at room temperature overnight and most of solvent was evaporated under reduced pressure. The residue was used for the addition reaction without further purification.
1-Boc-4-(3-mercaptopropanyl)piperazine




To a suspension of piperizaine (30.00 g, 348.27 mmol) and sodium carbonate (106 g, 348.27 mmol) in dichloromethane (200 ml) was added dropwise a solution of Di-tert-butyl dicarbonate (18.98 g, 87.07 mmol) in dichloromethane (30 ml) at room temperature for one hour. Then the mixture was stirred at room temperature overnight. The mixture was mixed with water (100 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in dichloromethane (100 ml). Sodium carbonate (15.44 g, 145.70 mmol) and 1-bromo-3-chloropropane (15.29 g, 97.13 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was mixed with water (80 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using hexane and ethyl acetate as eluent to give 11.77 g of 1-Boc-4-(3-chloropropanyl)piperazine.
To a solution of 1-Boc-4-(3-chloropropanyl)piperazine (11.77 g, 44.90 mmol) in ethanol (100 ml) was added thiourea (6.82 g, 89.80 mmol). The mixture was heated to reflux for 4 hours. A solution of sodium hydroxide (2.69 g, 67.35 mmol) in water (40 ml) was added, and the mixture was continued to reflux for another 2 hours. Then most solvent was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml) and brine (50 ml) and separated. The ethyl acetate was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using hexane and acetone as eluent to give 7.5 g of tert-butyl 4-N-Boc-1-(3-mercaptopropanyl)piperazine.
Examples 185-1836
Cyclosporin Derivatives
The following compounds can be prepared according to a method analogous to those described herein.







TABLE 1













 










Ex.





No.
W
Ra
Name





185
S




[(S)-(Carboxymethylthio)methyl- Sar]-3-cyclosporin


 


186
S




[(S)-(Carboxymethylthio)methyl- Sar]-3-cyclosporin-potassium salt


 


187
S




[(S)-(Carboxymethylthio)methyl-Sar]- 3-cyclosporin-sodium salt


 


188
S




[(S)-(Ethoxycarbonylmethylthio) methyl-Sar]-3-cyclosporin


 


189
S




[(S)-(2-Hydroxyethylthio) methyl-Sar]-3-cyclosporin


 


190
S




[(S)-(2-Hydroxy-2-methylpropylthio) methyl-Sar]-3-cyclosporin


 


191
S




[(S)-(2-(N-Isopropylamino)ethylthio) methyl-Sar]-3-cyclosporin


 


192
S




[(S)-(2-(N-Methyl-N-isopropylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


193
S




[(S)-(2-(N-Ethyl-N-isopropylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


194
S




[(S)-(2-(N-Isobutylamino)ethylthio) methyl-Sar]-3-cyclosporin


 


195
S




[(S)-(2-(N-Methyl-N-isobutylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


196
S




[(S)-(2-(N-Ethyl-N-isobutylamino) ethylthio)methyl-Sar]-3-cyclosporin 


 


197
S




[(S)-(2-(N-Neopentylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


198
S




[(S)-(2-(N-Methyl-N-Neopentylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


199
S




[(S)-(2-(N-Ethyl-N-Neopentylamino) ethylthio)methyl-Sar]-3-cyclosporin


 


200
S




[(S)-(2-(N-Piperidinyl)ethylthio) methyl-Sar]-3-cyclosporin


 


201
S




[(S)-(2-(N-Pyrrolidinyl)ethylthio) methyl-Sar]-3-cyclosporin


 


202
S




[(S)-(2-(N-Oxazolidinyl)ethylthio) methyl-Sar]-3-cyclosporin


 


203
S




[(S)-(2-(N-morpholino)ethylthio) methyl-Sar]-3-cyclosporin


 


204
S




[(S)-(2-(N-Thiazolidinyl)ethylthio) methyl-Sar]-3-cyclosporin


 


205
S




[(S)-(2-(N-Thiomorpholino)ethylthio) methyl-Sar]-3-cyclosporin


 


206
S




[(S)-(2-(N-Piperazinyl)ethylthio) methyl-Sar]-3-cyclosporin


 


207
S




[(S)-(2-(4-Methyl-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


208
S




[(S)-(2-(4-Ethyl-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


209
S




[(S)-(2-(4-Isopropyl-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


210
S




[(S)-(2-(4-Isobutyl-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


211
S




[(S)-(2-(4-Neopentyl-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


212
S




[(S)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl) ethylthio)methyl-Sar]-3-cyclosporin


 


213
S




[(S)-(2-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-cyclosporin


 


214
S




[(S)-(2-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-cyclosporin


 


215
S




[(S)-(2-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-cyclosporin


 


216
S




[(S)-(2-Carboxyethylthio) methyl-Sar]-3-cyclosporin


 


217
S




[(S)-(2-Carboxyethylthio)methyl-Sar]-3- cyclosporin-sodium salt 


 


218
S




[(S)-(2-(Ethoxycarbonyl)ethylthio)methyl- Sar]-3-cyclosporin


 


219
S




[(S)-(3-Hydroxypropylthio)methyl- Sar]-3-cyclosporin


 


220
S




[(S)-(3-Hydroxy-3-methylbutylthio) methyl-Sar]-3-cyclosporin


 


221
S




[(S)-(3-(N,N-Dimethylamino)propylthio) methyl-Sar]-3-cyclosporin


 


222
S




[(S)-(3-(N,N-Diethylamino)propylthio) methyl-Sar]-3-cyclosporin


 


223
S




[(S)-(3-(N-Isopropylamino)propylthio) methyl-Sar]-3-cyclosporin


 


224
S




[(S)-(3-(N-Isopropyl-N-methylamino)propylthio) methyl-Sar]-3-cyclosporin


 


225
S




[(S)-(3-(N-Ethyl-N-isopropylamino) propylthio)methyl-Sar]-3-cyclosporin


 


226
S




[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3- cyclosporin


 


227
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio) methyl-Sar]-3-cyclosporin


 


228
S




[(S)-(3-(N-Ethyl-N-isobutylamino)propylthio) methyl-Sar]-3-cyclosporin


 


229
S




[(S)-(3-(N,N-Diisobutylamino) propylthio)methyl-Sar]-3-cyclosporin


 


230
S




[(S)-(3-(N-Neopentylamino) propylthio)methyl-Sar]-3-cyclosporin


 


231
S




[(S)-(3-(N-Methyl-N-neopentylamino) propylthio)methyl-Sar]-3-cyclosporin


 


232
S




[(S)-(3-(N-Ethyl-N-neopentylamino)propylthio) methyl-Sar]-3-cyclosporin


 


233
S




[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]- 3-cyclosporin


 


234
S




[(S)-(3-(N-Thiazolidinyl)propylthio)methyl-Sar]-3- cyclosporin


 


235
S




[(S)-(3-(N-Thiomorpholino)propylthio) methyl-Sar]-3-cyclosporin


 


236
S




[(S)-(3-(N-Oxazolidinyl)propylthio) methyl-Sar]-3-cyclosporin


 


237
S




[(S)-(3-(N-Morpholino)propylthio)methyl- Sar]-3-cyclosporin


 


238
S




[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]- 3-cyclosporin


 


239
S




[(S)-(3-(4-Piperazinyl)propylthio)methyl-Sar]- 3-cyclosporin


 


240
S




[(S)-(3-(4-Methyl-N-piperazinyl)propylthio) methyl-Sar]-3-cyclosporin


 


241
S




[(S)-(3-(4-Ethyl-N-piperazinyl) propylthio)methyl-Sar]-3-cyclosporin


 


242
S




[(S)-(3-(4-n-Propyl-N-piperazinyl) propylthio)methyl-Sar]-3-cyclosporin


 


243
S




[(S)-(3-(4-Isopropyl-N-piperazinyl) propylthio)methyl-Sar]-3-cyclosporin


 


244
S




[(S)-(3-(4-Isobutyl-N-piperazinyl) propylthio)methyl-Sar]-3-cyclosporin


 


245
S




[(S)-(3-(4-Neopentyl-N-piperazinyl) propylthio)methyl-Sar]-3-cyclosporin


 


246
S




[(S)-(3-(4-(2-Hydroxyethyl)-N- piperazinyl)propylthio)methyl-Sar]-3- cyclosporin


 


247
S




[(S)-(3-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)propylthio)methyl-Sar]-3- cyclosporin


 


248
S




[(S)-(3-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)propylthio)methyl-Sar]-3- cyclosporin


 


249
S




[(S)-(3-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)propylthio)methyl-Sar]-3- cyclosporin


 


250
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-cyclosporin


 


251
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-cyclosporin-potassium salt


 


252
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-cyclosporin-sodium salt


 


253
S




[(S)-(3-(Ethoxycarbonyl)propylthio)methyl- Sar]-3-cyclosporin


 


254
S




[(S)-(4-Hydroxybutylthio) methyl-Sar]-3-cyclosporin


 


255
S




[(S)-(4-Hydroxy-(3-hydroxymethyl) butylthio)methyl-Sar]-3-cyclosporin


 


256
S




[S)-(4-Hydroxy-4-methylpentylthio) methyl-Sar]-3-cyclosporin


 


257
S




[(S)-(4-(N,N-Dimethylamino)butylthio) methyl-Sar]-3-cyclosporin


 


258
S




[(S)-(4-(N,N-Diethylamino)butylthio) methyl-Sar]-3-cyclosporin


 


259
S




[(S)-(4-(N-Isopropylamino)butylthio) methyl-Sar]-3-cyclosporin


 


260
S




[(S)-(4-(N-Isopropyl-N-methylamino) butylthio)methyl-Sar]-3-cyclosporin


 


261
S




[(S)-(4-(N-Ethyl-N-isopropylamino)butylthio) methyl-Sar]-3-cyclosporin


 


262
S




[(S)-(4-(N-Isobutylamino)butylthio) methyl-Sar]-3-cyclosporin


 


263
S




[(S)-(4-(N-Isobutyl-N-methylamino)butylthio) methyl-Sar]-3-cyclosporin


 


264
S




[(S)-(4-(N-Isobutyl-N-ethylamino)butylthio) methyl-Sar]-3-cyclosporin


 


265
S




[(S)-(4-(N,N-Diisobutylamino)butylthio) methyl-Sar]-3-cyclosporin


 


266
S




[(S)-(4-(N-Neopentylamino)butylthio) methyl-Sar]-3-cyclosporin


 


267
S




[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio) methyl-Sar]-3-cyclosporin


 


268
S




[(S)-(4-(N-Ethyl-N-Neopentylamino)butylthio) methyl-Sar]-3-cyclosporin


 


269
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl- Sar]-3-cyclosporin


 


270
S




[(S)-(4-N-Thiazolidinyl)butylthio)methyl- Sar]-3-cyclosporin


 


271
S




[(S)-(4-(N-Oxazolidinyl)butylthio)methyl- Sar]-3-cyclosporin


 


272
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]- 3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin


 


273
S




[(S)-(4-(N-Morpholino)butylthio)methyl- Sar]-3-cyclosporin


 


274
S




[(S)-(4-(N-Thiomorpholino)butylthio) methyl-Sar]-3-cyclosporin


 


275
S




[S)-(4-(N-Piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


276
S




[(S)-(4-(4-Methyl-N-piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


277
S




[(S)-(4-(4-Ethyl-N-piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


278
S




[(S)-(4-(4-n-Propyl-N-piperazinyl) butylthio)methyl-Sar]-3-cyclosporin


 


279
S




[(S)-(4-(4-Isopropyl-N-piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


280
S




[(S)-(4-(4-Isobutyl-N-piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


281
S




[(S)-(4-(4-Neopentyl-N-piperazinyl)butylthio) methyl-Sar]-3-cyclosporin


 


282
S




[(S)-(4-(4-(2-Hydroxyethyl)-N-piperazinyl) butylthio)methyl-Sar]-3-cyclosporin


 


283
S




[(S)-(4-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)butylthio)methyl-Sar]-3-cyclosporin


 


284
S




[(S)-(4-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)butylthio)methyl-Sar]-3-cyclosporin


 


285
S




[(S)-(4-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)butylthio)methyl-Sar]-3-cyclosporin


 


286
S




[(S)-(4-Carboxybutylthio) methyl-Sar]-3-cyclosporin


 


287
S




[(S)-(4-Carboxybutylthio) methyl-Sar]-3-cyclosporin- potassium salt


 


288
S




[(S)-(4-Carboxybutylthio)methyl-Sar]-3- cyclosporin-sodium salt


 


289
S




[(S)-(4-(Ethoxycarbonyl)butylthio)methyl- Sar]-3-cyclosporin


 


290
S




[(S)-(5-Hydroxypentylthio)methyl- Sar]-3-cyclosporin


 


291
S




[(S)-(5-Carboxypentylthio)methyl- Sar]-3-cyclosporin


 


292
S




[(S)-(5-Carboxypentylthio)methyl- Sar]-3-cyclosporin-potassium salt


 


293
S




[(S)-(5-Carboxypentylthio)methyl-Sar]- 3-cyclosporin-sodium salt


 


294
S




[(S)-(5-Ethoxycarbonyl)pentylthio) methyl-Sar]-3-cyclosporin


 


295
S




[(S)-(4-Carboxyhexylthio)methyl- Sar]-3-cyclosporin


 


296
S




[(S)-(4-Carboxyhexylthio)methyl-Sar]- 3-cyclosporin-potassium salt


 


297
S




[(S)-(4-Carboxyhexylthio)methyl-Sar]- 3-cyclosporin-sodium salt


 


298
S




[(S)-(4-(Ethoxycarbonyl)hexylthio) methyl-Sar]-3-cyclosporin


 


299
S




[(S)-(5-Carboxyheptylthio)methyl- Sar]-3-cyclosporin


 


300
S




[(S)-(5-Carboxyheptylthio)methyl-Sar]-3- cyclosporin-potassium salt


 


301
S




[(S)-(5-Carboxyheptylthio)methyl-Sar]- 3-cyclosporin-sodium salt


 


302
S




[(S)-(5-Ethoxycarbonyl)heptylthio)methyl-Sar]-3- cyclosporin


 


303
S




[(S)-(5-Carboxyoctylthio)methyl-Sar]-3- cyclosporin


 


304
S




[(S)-(5-Carboxyoctylthio)methyl-Sar]-3- cyclosporin-potassium salt


 


305
S




[(S)-(5-Carboxyoctylthio)methyl-Sar]-3- cyclosporin-potassium salt


 


306
S




[(S)-(4-Ethoxycarbonyl)octylthio)methyl- Sar]-3-cyclosporin


 


307
S




[(S)-(5-Carboxynonylthio)methyl-Sar]- 3-cyclosporin


 


308
S




[(S)-(5-Carboxynonylthio)methyl-Sar]- 3-cyclosporin-potassium salt


 


309
S




[(S)-(5-Carboxynonylthio)methyl-Sar]- 3-cyclosporin-potassium salt


 


310
S




[(S)-(4-(Ethoxycarbonyl)nonylthio)methyl- Sar]-3-cyclosporin


 


311
S




[(S)-((4,4′-Dicarboxy)butylthio) methyl-Sar]-3-cyclosporin


 


312
S




[(S)-((4,4′-Dicarboxy)butylthio) methyl-Sar]-3-cyclosporin-dipotassium salt


 


313
S




[(S)-((4,4′-Dicarboxy)butylthio) methyl-Sar]-3-cyclosporin-disodium salt


 


314
S




[(S)-(4,4′-Diethoxycarbonyl) butylthio)methyl-Sar]-3-cyclosporin


 


315
S




[(S)-((5,5′-Dicarboxy)pentylthio) methyl-Sar]-3-cyclosporin


 


316
S




[(S)-((5,5′-Dicarboxy)pentylthio) methyl-Sar]-3-cyclosporin-dipotassium salt


 


317
S




[(S)-((5,5′-Dicarboxy)pentylthio) methyl-Sar]-3-cyclosporin-disodium salt


 


318
S




[(S)-(4,4′-Diethoxycarbonyl) pentylthio)methyl-Sar]-3-cyclosporin


 


319
S




[(S)-(6-Hydroxyhexylthio)methyl- Sar]-3-cyclosporin


 


320
S




[(S)-((6,6′-Dicarboxy)hexylthio) methyl-Sar]-3-cyclosporin


 


321
S




[(S)-((6,6′-Dicarboxy)hexylthio)methyl- Sar]-3-cyclosporin-dipotassium salt


 


322
S




[(S)-((6,6′-Dicarboxy)hexylthio)methyl- Sar]-3-cyclosporin-disodium salt


 


323
S




[(S)-(6,6′-Diethoxycarbonyl)hexylthio) methyl-Sar]-3-cyclosporin


 


324
S




[(S)-((7,7′-Dicarboxy)heptylthio)methyl- Sar]-3-cyclosporin


 


325
S




[(S)-((7,7′-Dicarboxy)heptylthio)methyl- Sar]-3-cyclosporin-dipotassium salt


 


326
S




[(S)-((7,7′-Dicarboxy)heptylthio)methyl- Sar]-3-cyclosporin-disodium salt


 


327
S




[(S)-(7,7′-Diethoxycarbonyl)heptylthio) methyl-Sar]-3-cyclosporin


 


328
S




[(S)-[(N-(2-Aminoethyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


329
S




[(S)-[(N-(2-(Neopentylamino)ethyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


330
S




[(S)-[(N-(3-Aminopropyl)carbamoyl) methylthio]methyl-Sar]- 3-cyclosporin


 


331
S




[(S)-[(N-(3-(Neopentylamino)propyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


332
S




[(S)-[(N-(4-Aminobutyl)carbamoyl) methylthio]methyl-Sar]- 3-cyclosporin


 


333
S




[(S)-[(N-(4-Neopentylamino)butyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


334
S




[(S)-[(N-(5-Aminopentyl)carbamoyl) methylthio]methyl-Sar]- 3-cyclosporin


 


335
S




[(S)-[(N-(5-(Neopentylamino)pentyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


336
S




[(S)-[(N-(6-Aminohexyl)carbamoyl) methylthio]methyl-Sar]- 3-cyclosporin


 


337
S




[(S)-[(N-(6-Neopentylamino)hexyl)carbamoyl) methylthio]methyl-Sar]-3-cyclosporin


 


338
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl) methylthio]methyl-Sar]- 3-cyclosporin


 


339
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl) ethylthio]methyl-Sar]-3- cyclosporin


 


340
S




[(S)-[([HO-Gly-(D-Glu6]carbamoyl) propylthio)methyl-Sar]- 3-cyclosporin


 


341
S




[(S)-((2-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]ethyl) sulfanyl)methyl-Sar]-3-cyclosporin


 


342
S




[(S)-((3-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]propyl)sulfanyl) methyl-Sar]-3-cyclosporin


 


343
S




[(S)-((4-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]butyl)sulfanyl) methyl-Sar]-3-cyclosporin


 


344
S




[(S)-((5-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]pentyl)sulfanyl) methyl-Sar]-3-cyclosporin


 


345
S




[(S)-((6-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]hexyl)sulfanyl)methyl- Sar]-3-cyclosporin


 


346
S




[(S)-(((R)-3-Hydroxymethyl-6-(imidazol-1- yl)hexyl)thio)methyl-Sar]-3-cyclosporin


 


347
S




[(S)-(((S)-3-Hydroxymethyl-6-(imidazo-1- yl)hexyl)thio)methyl-Sar]-3-cyclosporin


 


348
S




[(S)-(((R)-3-Hydroxymethyl-6- morpholinohexyl)thio)methyl- Sar]-3-cyclosporin


 


349
S




[(S)-(((S)-3-Hydroxymethyl-6- morpholinohexyl)thio)methyl- Sar]-3-cyclosporin


 


350
S




[(S)-(((R)-3-Hydroxymethyl-6-(4- methylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-cyclosporin


 


351
S




[(S)-(((S)-3-Hydroxymethyl-6- (4-methylpiperazin-1-yl)hexyl) thio)methyl-Sar]-3-cyclosporin


 


352
S




[(S)-(((R)-3-Hydroxymethyl-6-(4-ethylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-cyclosporin


 


353
S




[(S)-(((S)-3-Hydroxymethyl-6-(4- isopropylpiperazin-1-yl)hexyl) thio)methyl-Sar]-3-cyclosporin


 


354
S




[(S)-(((S)-4-Hydroxy-7-(imidazol-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


355
S




[(S)-(((R)-4-Hydroxy-7-(imidazo-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


356
S




[(S)-(((S)-4-Hydroxy-7-morpholinoheptyl) thio)methyl-Sar]-3-cyclosporin


 


357
S




[(S)-(((R)-4-Hydroxy-7-morpholinoheptyl) thio)methyl-Sar]-3-cyclosporin


 


358
S




[(S)-(((S)-4-Hydroxy-7-(4-methylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


359
S




[(S)-(((R)-4-Hydroxy-7-(4-methylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


360
S




[(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


361
S




[(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-cyclosporin


 


362
O




[(R)-(Carboxymethyloxy)methyl-Sar]- 3-cyclosporin-potassium salt


 


363
O




[(R)-(2-Hydroxy-2,2-dimethylethoxy) methyl-Sar]-3-cyclosporin


 


364
O




[(R)-(2-(Isopropylamino)ethoxy)methyl- Sar]-3-cyclosporin


 


365
O




[(R)-(2-(N-Isopropyl-N-methylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


366
O




[(R)-(2-(N-Ethyl-N-isopropylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


367
O




[(R)-(2-(N-Isobutylamino)ethoxy) methyl-Sar]-3-cyclosporin


 


368
O




[(R)-(2-(N-Isobutyl-N-methylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


369
O




[(R)-(2-(N-Ethyl-N-isobutylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


370
O




[(R)-(2-(N-Neopentylamino)ethoxy) methyl-Sar]-3-cyclosporin


 


371
O




[(R)-(2-(N-Methyl-N-Neopentylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


372
O




[(R)-(2-(N-Ethyl-N-Neopentylamino) ethoxy)methyl-Sar]-3-cyclosporin


 


373
O




[(R)-(2-(N-Oxazolidinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


374
O




[(R)-(2-(N-Thiazolidinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


375
O




[(R)-(2-(N-Thiomorpholino)ethoxy) methyl-Sar]-3-cyclosporin


 


376
O




[(R)-(2-(N-Piperazinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


377
O




[(R)-(2-(4-Methyl-N-piperazinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


378
O




[(R)-(2-(4-Ethyl-N-piperazinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


379
O




[(R)-(2-(4-Isopropyl-N-piperazinyl) ethoxy)methyl-Sar]-3-cyclosporin


 


380
O




[(R)-(2-(4-Isobutyl-N-piperazinyl)ethoxy) methyl-Sar]-3-cyclosporin


 


381
O




[(R)-(2-(4-Neopentyl-N-piperazinyl) ethoxy)methyl-Sar]-3-cyclosporin


 


382
O




[(R)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-cyclosporin


 


383
O




[(R)-(2-(4-(2-Hydroxy-2-methylpropyl)- N-piperazinyl)ethoxy)methyl- Sar]-3-cyclosporin


 


384
O




[(R)-(2-(4-(3-Hydroxy-3-methylbutyl)- N-piperazinyl)ethoxy)methyl- Sar]-3-cyclosporin


 


385
O




[(R)-(2-(4-(4-Hydroxy-4-methylpentyl)- N-piperazinyl)ethoxy)methyl- Sar]-3-cyclosporin


 


386
O




[(R)-(2-Carboxyethoxy)methyl-Sar]- 3-cyclosporin


 


387
O




[(R)-(2-Carboxyethoxy)methyl- Sar]-3-cyclosporin-sodium salt


 


388
O




[(R)-(2-(Ethoxycarbonyl)ethoxy) methyl-Sar]-3-cyclosporin


 


389
O




[(R)-(3-Hydroxypropoxy)methyl- Sar]-3-cyclosporin


 


390
O




[(R)-(3-Hydroxy-3-methylbutoxy) methyl-Sar]-3-cyclosporin


 


391
O




[(R)-(3-(N-Isopropylamino) propoxy)methyl-Sar]-3-cyclosporin


 


392
O




[(R)-(3-(N-Isopropyl-N-methylamino) propoxy)methyl-Sar]-3-cyclosporin


 


393
O




[(R)-(3-(N-Ethyl-N-isopropylamino) propoxy)methyl-Sar]-3-cyclosporin


 


394
O




[(R)-(3-(N-Neopentylamino) propoxy)methyl-Sar]-3-cyclosporin


 


395
O




[(R)-(3-(N-Methyl-N-Neopentylamino) propoxy)methyl-Sar]-3-cyclosporin


 


396
O




[(R)-(3-(N-Ethyl-N-Neopentylamino) propoxy)methyl-Sar]-3-cyclosporin


 


397
O




[(R)-(3-(N-Thiazolidinyl) propoxymethyl-Sar]-3-cyclosporin


 


398
O




[(R)-(3-(N-Thiomorpholino) propoxy)methyl-Sar]-3-cyclosporin


 


399
O




[(R)-(3-(N-Piperazinyl)propoxy) methyl-Sar]-3-cyclosporin


 


400
O




[(R)-(3-(4-Methyl-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


401
O




[(R)-(3-(4-Ethyl-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


402
O




[(R)-(3-(4-Isopropyl-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


403
O




[(R)-(3-(4-Isobutyl-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


404
O




[(R)-(3-(4-Neopentyl-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


405
O




[(R)-(3-(4-(2-Hydroxyethyl)-N-piperazinyl) propoxy)methyl-Sar]-3-cyclosporin


 


406
O




[(R)-(3-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)propoxy)methyl- Sar]-3-cyclosporin


 


407
O




[(R)-(3-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)propoxy)methyl- Sar]-3-cyclosporin


 


408
O




[(R)-(3-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)propoxy)methyl-Sar]- 3-cyclosporin


 


409
O




[(R)-(3-Carboxypropoxy)methyl- Sar]-3-cyclosporin


 


410
O




[(R)-(3-Carboxypropoxy)methyl- Sar]-3-cyclosporin-potassium salt


 


411
O




[(R)-(3-Carboxypropoxy)methyl-Sar]- 3-cyclosporin-sodium salt


 


412
O




[(R)-(3-(Ethoxycarbonyl)propoxy) methyl-Sar]-3-cyclosporin


 


413
O




[(R)-(4-Hydroxybutoxy)methyl- Sar]-3-cyclosporin


 


414
O




[(R)-(4-Hydroxy-4-methylpentyloxy) methyl-Sar]-3-cyclosporin


 


415
O




[(R)-(4-(N,N-Dimethylamino)butoxy) methyl-Sar]-3-cyclosporin


 


416
O




[(R)-(4-(N,N-Diethylamino)butoxy) methyl-Sar]-3-cyclosporin


 


417
O




[(R)-(4-(N-Isopropylamino)butoxy) methyl-Sar]-3-cyclosporin


 


418
O




[(R)-(4-(N-Isopropyl-N-methylamino) butoxy)methyl-Sar]-3-cyclosporin


 


419
O




[(R)-(4-(N-Ethyl-N-isopropylamino) butoxy)methyl-Sar]-3-cyclosporin


 


420
O




[(R)-(4-(N-Isobutylamino)butoxy) methyl-Sar]-3-cyclosporin


 


421
O




[(R)-(4-(N-Isobutyl-N-methylamino) butoxy)methyl-Sar]-3-cyclosporin


 


422
O




[(R)-(4-(N-Ethyl-N-isobutylamino) butoxy)methyl-Sar]-3-cyclosporin


 


423
O




[(R)-(4-(N,N-Diisobutylamino) butoxy)methyl-Sar]-3-cyclosporin


 


424
O




[(R)-(4-(N-Neopentylamino)butoxy) methyl-Sar]-3-cyclosporin


 


425
O




[(R)-(4-(N-Methyl-N-neopentylamino) butoxy)methyl-Sar]-3-cyclosporin


 


426
O




[(R)-(4-(N-Ethyl-N-neopentylamino) butoxy)methyl-Sar]-3-cyclosporin


 


427
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl- Sar]-3-cyclosporin


 


428
O




[(R)-(4-(N-Thiazolidinyl)butoxy)methyl- Sar]-3-cyclosporin


 


429
O




[(R)-(4-(N-Oxazolidinyl)butoxy)methyl- Sar]-3-cyclosporin


 


430
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl- Sar]-3-cyclosporin


 


431
O




[(R)-(4-(N-Morpholino)butoxy)methyl- Sar]-3-cyclosporin


 


432
O




[(R)-(4-(N-Thiomorpholino)butoxy) methyl-Sar]-3-cyclosporin


 


433
O




[(R)-(4-(N-Piperazinyl)butoxy) methyl-Sar]-3-cyclosporin


 


434
O




[(R)-(4-(4-Methyl-N-piperazinyl)butoxy) methyl-Sar]-3-cyclosporin


 


435
O




[(R)-(4-(4-Ethyl-N-piperazinyl)butoxy) methyl-Sar]-3-cyclosporin


 


436
O




[(R)-(4-(4-n-Propyl-N-piperazinyl)butoxy) methyl-Sar]-3-cyclosporin


 


437
O




[(R)-(4-(4-Isopropyl-N-piperazinyl) butoxy)methyl-Sar]-3-cyclosporin


 


438
O




[(R)-(4-(4-Isobutyl-N-piperazinyl) butoxy)methyl-Sar]-3-cyclosporin


 


439
O




[(R)-(4-(4-Neopentyl-N-piperazinyl)butoxy) methyl-Sar]-3-cyclosporin


 


440
O




[(R)-(4-(4-(2-Hydroxyethyl)-N-piperazinyl) butoxy)methyl-Sar]-3-cyclosporin


 


441
O




[(R)-(4-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)butoxy)methyl-Sar]-3-cyclosporin


 


442
O




[(R)-(4-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)butoxy)methyl-Sar]-3-cyclosporin


 


443
O




[(R)-(4-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)butoxy)methyl-Sar]-3-cyclosporin


 


444
O




[(R)-(4-Carboxybutoxy)methyl- Sar]-3-cyclosporin


 


445
O




[(R)-(4-Carboxybutoxy)methyl-Sar]- 3-cyclosporin-potassium salt


 


446
O




[(R)-(4-Carboxybutoxy)methyl-Sar]- 3-cyclosporin-sodium salt


 


447
O




[(R)-(4-(Ethoxycarbonyl)butoxy) methyl-Sar]-3-cyclosporin


 


448
O




[(R)-(5-(Carboxypentyl)oxy) methyl-Sar]-3-cyclosporin


 


449
O




[(R)-(5-(Carboxypentyl)oxy)methyl- Sar]-3-cyclosporin-potassium salt


 


450
O




[(R)-(5-(Carboxypentyl)oxy)methyl- Sar]-3-cyclosporin-sodium salt


 


451
O




[(R)-(((5-(Ethoxycarbonyl)pentyl)oxy) methyl-Sar]-3-cyclosporin


 


452
O




[(R)-(5-Carboxyheptyloxy)methyl- Sar]-3-cyclosporin


 


453
O




[(R)-(5-Carboxyheptyloxy)methyl-Sar]- 3-cyclosporin-potassium salt


 


454
O




[(R)-(5-Carboxyheptyloxy)methyl-Sar]- 3-cyclosporin-sodium salt


 


455
O




[(R)-(5-Ethoxycarbonyl)heptyloxy) methyl-Sar]-3-cyclosporin


 


456
O




[(R)-(5-Carboxyoctyloxy)methyl- Sar]-3-cyclosporin


 


457
O




[(R)-(5-Carboxyoctyloxy)methyl- Sar]-3-cyclosporin-potassium salt


 


458
O




[(R)-(5-Carboxyoctyloxy)methyl- Sar]-3-cyclosporin-potassium salt


 


459
O




[(R)-(4-(Ethoxycarbonyl)octyloxy) methyl-Sar]-3-cyclosporin


 


460
O




[(R)-(5-Carboxynonyloxy)methyl- Sar]-3-cyclosporin


 


461
O




[(R)-(5-Carboxynonyloxy)methyl-Sar]- 3-cyclosporin-potassium salt


 


462
O




[(R)-(5-Carboxynonyloxy)methyl-Sar]- 3-cyclosporin-potassium salt


 


463
O




[(R)-(4-(Ethoxycarbonyl)nonyloxy) methyl-Sar]-3-cyclosporin


 


464
O




[(R)-((4,4′-Dicarbonyl)butoxy)methyl- Sar]-3-cyclosporin


 


465
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]- 3-cyclosporin-dipostassium salt


 


466
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]- 3-cyclosporin-disodium salt


 


467
O




[(R)-(4,4′-Di(ethoxycarbonyl)butoxy) methyl-Sar]-3-cyclosporin


 


468
O




[(R)-((5,5′-Dicarboxy)pentyloxy) methyl-Sar]-3-cyclosporin


 


469
O




[(R)-((5,5′-Dicarboxy)pentyloxymethyl- Sar]-3-cyclosporin-dipotassium salt


 


470
O




[(R)-((5,5′-Dicarboxy)pentyloxy)methyl- Sar]-3-cyclosporin-disodium salt


 


471
O




[(R)-(4,4′-Diethoxycarbonyl)pentyloxy) methyl-Sar]-3-cyclosporin


 


472
O




[(R)-((6,6′-Dicarboxy)hexyloxy) methyl-Sar]-3-cyclosporin


 


473
O




[(R)-((6,6′-Dicarboxy)hexyloxy)methyl- Sar]-3-cyclosporin-dipotassium salt


 


474
O




[(R)-((6,6′-Dicarboxy)hexyloxy)methyl- Sar]-3-cyclosporin-disodium salt


 


475
O




[(R)-(6,6′-Diethoxycarbonyl)hexyloxy) methyl-Sar]-3-cyclosporin


 


476
O




[(R)-((7,7′-Dicarboxy)heptyloxy) methyl-Sar]-3-cyclosporin


 


477
O




[(R)-((7,7′-Dicarboxy)heptyloxy) methyl-Sar]-3-cyclosporin-dipotassium salt


 


478
O




[(R)-((7,7′-Dicarboxy)heptyloxy) methyl-Sar]-3-cyclosporin-disodium salt


 


479
O




[(R)-(7,7′-Diethoxycarbonyl) heptyloxy)methyl-Sar]-3- cyclosporin


 


480
O




[(R)-((R)-3-Hydroxymethyl-4- ethoxycarbonylbutoxy)methyl- Sar]-3-cyclosporin


 


481
O




[(R)-((R)-3-Methoxymethyl-4- ethoxycarbonylbutoxy)methyl- Sar]-3-cyclosporin


 


482
O




[(R)-((S)-3-Hydroxymethyl-4- ethoxycarbonylbutoxy)methyl- Sar]-3-cyclosporin


 


483
O




[(R)-((S)-3-Methoxymethyl-4- ethoxycarbonylbutoxy)methyl- Sar]-3-cyclosporin


 


484
O




[(R)-(5-Hydroxypentyloxy) methyl-Sar]-3-cyclosporin


 


485
O




[(R)-(6-Hydroxyhexyloxy) methyl-Sar]-3-cyclosporin


 


486
O




[(R)-[(N-(2-Aminoethyl)carbamoyl) methoxy]methyl-Sar]-3- cyclosporin


 


487
O




[(R)-[(N-(2-(Neopentylamino) ethyl)carbamoyl)methoxy] methyl-Sar]-3-cyclosporin


 


488
O




[(R)-[(N-(3-Aminopropyl)carbamoyl) methoxy]methyl-Sar]-3- cyclosporin


 


489
O




[(R)-[(N-(3-(Neopentylamino) propyl)carbamoyl)methoxy] methyl-Sar]-3-cyclosporin


 


490
O




[(R)-[(N-(4-Aminobutyl)carbamoyl) methoxy]methyl-Sar]-3-cyclosporin


 


491
O




[(R)-[(N-(4-(Neopentylamino)butyl) carbamoyl)methoxy]methyl-Sar]-3- cyclosporin


 


492
O




[(R)-[(N-(5-Aminopentyl)carbamoyl) methoxy]methyl-Sar]-3- cyclosporin


 


493
O




[(R)-[(N-(5-(Neopentylamino) pentyl)carbamoyl) methoxy]methyl-Sar]-3-cyclosporin


 


494
O




[(R)-[(N-(6-Aminohexyl)carbamoyl) methoxy]methyl-Sar]-3- cyclosporin


 


495
O




[(R)-[(N-(6-(Neopentylamino)hexyl) carbamoyl)methoxy]methyl-Sar]-3- cyclosporin


 


496
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]methyl-Sar]-3-cyclosporin


 


497
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl) ethoxy]methyl-Sar]-3-cyclosporin


 


498
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl) propoxy]methyl-Sar]-3-cyclosporin


 


499
O




[(R)-((2-[([HO-Gly-(D- Glu)6]carbamoyl)methoxy]ethoxy) methyl-Sar]-3-cyclosporin


 


500
O




[(R)-((3-[([HO-Gly-(D- Glu)6]carbamoyl)methoxy]propoxy) methyl-Sar]-3-cyclosporin


 


501
O




[(R)-((4-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]butoxy)methyl-Sar]-3- cyclosporin


 


502
O




[(R)-((5-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]pentyloxy) methyl-Sar]-3-cyclosporin


 


503
O




[(R)-((6-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]hexyloxy)methyl-Sar]-3- cyclosporin


 


504
O




[(R)-(((R)-3-Hydroxymethyl-6-(imidazol-1- yl)hexyl)oxy)methyl-Sar]-3-cyclosporin


 


505
O




[(R)-(((S)-3-Hydroxymethyl-6-(imidazo-1- yl)hexyl)oxy)methyl-Sar]-3-cyclosporin


 


506
O




[(R)-(((R)-3-Hydroxymethyl-6- morpholinohexyl)oxy)methyl- Sar]-3-cyclosporin


 


507
O




[(R)-(((S)-3-Hydroxymethyl-6- morpholinohexyl)oxy)methyl- Sar]-3-cyclosporin


 


508
O




[(R)-(((R)-3-Hydroxymethyl-6-(4- methylpiperazin-1-yl)hexyl)oxy) methyl-Sar]-3-cyclosporin


 


509
O




[(R)-(((S)-3-Hydroxymethyl-6-(4- methylpiperazin-1-yl)hexyl) oxy)methyl-Sar]-3-cyclosporin


 


510
O




[(R)-(((R)-3-Hydroxymethyl-6-(4- ethylpiperazin-1-yl)hexyl)oxy) methyl-Sar]-3-cyclosporin


 


511
O




[(R)-(((S)-3-Hydroxymethyl-6-(4- isopropylpiperazin-1-yl)hexyl) oxy)methyl-Sar]-3-cyclosporin


 


512
O




[(R)-(((S)-4-Hydroxy-7-(imidazol- 1-yl)heptyl)oxy)methyl- Sar]-3-cyclosporin


 


513
O




[(R)-(((R)-4-Hydroxy-7-(imidazo- 1-yl)heptyl)oxy)methyl- Sar]-3-cyclosporin


 


514
O




[(R)-(((S)-4-Hydroxy-7- morpholinoheptyl)oxy)methyl-Sar]- 3-cyclosporin


 


515
O




[(R)-(((R)-4-Hydroxy-7- morpholinoheptyl)oxy)methyl-Sar]- 3-cyclosporin


 


516
O




[(R)-(((S)-4-Hydroxy-7-(4- methylpiperazin-1-yl)heptyl)oxy) methyl-Sar]-3-cyclosporin


 


517
O




[(R)-(((R)-4-Hydroxy-7-(4- methylpiperazin-1-yl)heptyl)oxy) methyl-Sar]-3-cyclosporin


 


518
O




[(R)-(((S)-4-Hydroxy-7-(4- ethylpiperazin-1-yl)heptylcyclos) oxy)methyl-Sar]-3-cyclosporin


 


519
O




[(R)-(((R)-4-Hydroxy-7-(4- ethylpiperazin-1-yl)heptyl)oxy) methyl-Sar]-3-cyclosporin


 


520
CH2
—(COOEt)2
[(R)-2,2-Di(ethoxycarbonyl)ethyl)-Sar]-3-





cyclosporin


521
CH2
—(COOH)2
[(R)-2,2-Di(carboxy)ethyl)-Sar]-3-cyclosporin


522
CH2
—(CH2OH)2
[(R)-2,2-Di(hydroxylmethyl)ethyl)-Sar]-3-





cyclosporin
















TABLE 2













 










Ex.





No.
W
Ra
Name





 523
S




[(S)-(Carboxymethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 524
S




[(S)-(Carboxymethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


 525
S




[(S)-(Carboxymethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


 526
S




[(S)-(Ethoxycarbonylmethylthio) methyl-Sar]-3-[(γ-hydroxy- N-MeLeu]-4-cyclosporin


 


 527
S




[(S)-(2-Hydroxy-2-methylpropylthio) methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 528
S




[(S)-(2-Methoxyethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 529
S




[(S)-(2-(N-Isobutylamino)ethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 530
S




[(S)-(2-(N-Isobutyl-N-methylamino)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 531
S




[(S)-(2-(N-Ethyl-N-isobutylamino)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 532
S




[(S)-(2-(N-Thiazolidinyl)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 533
S




[(S)-(2-(N-Oxazolidinyl)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 534
S




[(S)-(2-(N-Thiomorpholino)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 535
S




[(S)-(2-(4-Isopropyl-N-piperazinyl)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 536
S




[(S)-(2-(4-Neopentyl-N-piperazinyl)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 537
S




[(S)-(2-(4-(2-Hydroxy-2-methylethyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 538
S




[(S)-(2-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)ethylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 539
S




[(S)-(2-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 540
S




[(S)-(2-(4-(2-Methoxyethyl)-N- piperazinyl)ethylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 541
S




[(S)-(2-(4-(2-Methoxy-2-methylpropyl)-N- piperazinyl)ethylthio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 542
S




[(S)-(2-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)ethylthio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 543
S




[(S)-(2-(4-(4-Methoxy-4-methylpentyl)-N- piperazinyl)ethylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 544
S




[(S)-(2-Carboxyethylthio) methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclospori


 


 545
S




[(S)-(2-Carboxyethylthio) methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin-sodium salt


 


 546
S




[(S)-((2-Ethoxycarbonyl)ethylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclospori


 


 547
S




[(S)-(3-(N-Isopropyl-N-methylamino)propylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 548
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 549
S




[(S)-(3-(N-Isobutyl-N-ethylamino)propylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 550
S




[(S)-(3-(N-Methyl-N-Neopentylamino)propylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 551
S




[(S)-(3-(N-Ethyl-N-Neopentylamino)propylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 552
S




[(S)-(3-(N-Thiazolidinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 553
S




[(S)-(3-(N-Oxazolidinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 554
S




[(S)-(3-(4-(2-Hydroxyethyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 555
S




[(S)-(3-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 556
S




[(S)-(3-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 557
S




[(S)-(3-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 558
S




[(S)-(3-(4-(2-Methoxyethyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 559
S




[(S)-(3-(4-(2-Methoxy-2-methylpropyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 560
S




[(S)-(3-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 561
S




[(S)-(3-(4-(4-Methoxy-4-methylpentyl)-N- piperazinyl)propylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 562
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 563
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin-potassium salt


 


 564
S




[(S)-(3-Carboxypropylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin-sodium salt


 


 565
S




[(S)-(3-Ethoxycarbonylpropylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 566
S




[(S)-(3-Isobutoxycarbonylpropylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 567
S




[(S)-((5-Hydroxy-2-methylpentan- 2-yl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 568
S




[(S)-((4-Hydroxy-2,2-dimethylbutyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 569
S




[(S)-((4-Hydroxy-3,3-dimethylbutyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 570
S




[(S)-(4-Methoxy-4-methylpentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 571
S




[(S)-(3-(1-Hydroxycyclopropyl) propylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 572
S




[(S)-(((2-(1-(Hydroxymethyl)cyclopropyl) ethyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 573
S




[(S)-(((1-(2-Hydroxyethyl)cyclopropyl) methyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 574
S




[(S)-((1-(3-Hydroxypropyl) cyclopropyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 575
S




[(S)-((S)-4-Hydroxyhexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 576
S




[(S)-((R)-4-Hydroxyhexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 577
S




[(S)-(((S)-3-(Hydroxymethyl)pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 578
S




[(S)-(((R)-3-(Hydroxymethyl)pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 579
S




[(S)-(((S)-2-Ethyl-4-hydroxybutyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 580
S




[(S)-(((R)-2-Ethyl-4-hydroxybutyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 581
S




[(S)-(((S)-4,5-Dihydroxy-pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 582
S




[(S)-(((R)-4,5-Dihydroxy-pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 583
S




[(S)-(((S)-4,5-Dihydroxy-4- methylpentyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 584
S




[(S)-(((R)-4,5-Dihydroxy-4- methylpentyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 585
S




[(S)-(((R)-4,6-Dihydroxyhexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 586
S




[(S)-(((S)-4,6-Dihydroxyhexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 587
S




[(S)-(((R)-5-Hydroxy-3-(hydroxymethyl) pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 588
S




[(S)-(((S)-5-Hydroxy-3-(hydroxymethyl) pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 589
S




[(S)-((4-Hydroxy-2-(2-hydroxyethyl)butyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 590
S




[(S)-((4-(Hydroxymethyl)pent-4-en-1-yl)thio) methyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 591
S




[(S)-((5-Hydroxy-3-methylenepentyl)thio) methyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 592
S




[(S)-((5-Hydroxy-2-methylenepentyl)thio) methyl)-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 593
S




[(S)-((2-(2-(Hydroxymethyl) oxiran-2-yl)ethyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 594
S




[(S)-(((2-(2-Hydroxyethyl)oxiran- 2-yl)methyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 595
S




[(S)-((3-(3-Hydroxyoxetan-3- yl)propyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 596
S




[(S)-((4,5-Dihydroxy-4-(hydroxymethyl) pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 597
S




[(S)-((3-(2-(Hydroxymethyl) oxiran-2-yl)propyl)thio)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 598
S




[(S)-((2-(2-Hydroxyethyl) oxiran-2-yl)ethyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 599
S




[(S)-(((2-(3-Hydroxypropyl) oxiran-2-yl)methyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 600
S




[(S)-((5-Hydroxy-4-oxohexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 601
S




[(S)-((6-Hydroxy-5-oxohexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 602
S




[(S)-((6-Hydroxy-5-oxohexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 603
S




[(S)-(((R)-4-Hydroxy-5-(pyrrolidin-1-yl) pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 604
S




[(S)-(((S)-4-Hydroxy-5-(pyrrolidin-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 605
S




[(S)-(((R)-4-Hydroxy-6-(pyrrolidin-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 606
S




[(S)-(((S)-4-Hydroxy-6-(piperidin-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 607
S




[(S)-(((R)-4-Hydroxy-5-(imidazol-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 608
S




[(S)-(((S)-4-Hydroxy-5-(imidazo-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 609
S




[(S)-(((R)-4-Hydroxy-6-(imidazo-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 610
S




[(S)-(((S)-4-Hydroxy-6-(imidazo-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 611
S




[(S)-(((R)-3-Hydroxymethyl-4-(imidazol-1- yl)butyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 612
S




[(S)-(((S)-3-Hydroxymethyl-4-(imidazo-1- yl)butyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 613
S




[(S)-(((R)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 614
S




[(S)-(((S)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 615
S




[(S)-(((R)-4-Hydroxy-5-(piperidin-1-yl)pentyl) thio)methy-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 616
S




[(S)-(((S)-4-Hydroxy-5-(piperidin-1-yl)pentyl) thio)methy-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 617
S




[(S)-(((R)-4-Hydroxy-5-(piperidin-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 618
S




[(S)-(((S)-4-Hydroxy-5-(piperidin-1-yl) hexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 619
S




[(S)-(((R)-4-Hydroxy-6-morpholinohexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 620
S




[(S)-(((S)-4-Hydroxy-6-morpholinohexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 621
S




[(S)-(((R)-2-(Hydroxymethyl)-4- morpholinobutyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 622
S




[(S)-(((S)-2-(Hydroxymethyl)-4- morpholinobutyl)thio)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 623
S




[(S)-(((S)-4-Hydroxy-2-(2- morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 624
S




[(S)-(((R)-4-Hydroxy-2-(2- morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 625
S




[(S)-(((S)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 626
S




[(S)-(((R)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 627
S




[(S)-(((S)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 628
S




[(S)-(((R)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 629
S




[(S)-(((R)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 630
S




[(S)-(((S)-4-Hydroxy-6-(4- isopropylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 631
S




[(S)-(((S)-3-Hydroxymethyl-5-(4- methylpiperazin-1-yl)pentyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]- 4-cyclosporin


 


 632
S




[(S)-(((R)-3-Hydroxymethyl-5- (4-methylpiperazin-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 633
S




[(S)-(((S)-3-Hydroxymethyl-5- (4-ethylpiperazin-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 634
S




[(S)-(((R)-3-Hydroxymethyl-5- (4-ethylpiperazin-1-yl)pentyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 635
S




[(S)-(((R)-3-Hydroxymethyl-5-(4- isopropylpiperazin-1-yl)pentyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 636
S




[(S)-(((S)-3-Hydroxymethyl-5- (4-isopropylpiperazin-1-yl)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 637
S




[(S)-(((R)-4-Hydroxy-5- (neopentylamino)pentyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 638
S




[(S)-(((S)-4-Hydroxy-5-(neopentylamino) pentyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 639
S




[(S)-(((S)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 640
S




[(S)-(((R)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 641
S




[(S)-(((S)-4-Hydroxy-2- ((neopentylamino)methyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 642
S




[(S)-(((R)-4-Hydroxy-2- ((neopentylamino)methyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 643
S




[(S)-(((R)-4-Hydroxy-6-(neopentylamino)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 644
S




[(S)-(((S)-4-Hydroxy-6-(neopentylamino)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 645
S




[(S)-(((R)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 646
S




[(S)-(((S)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 647
S




[(S)-(((R)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 648
S




[(S)-(((S)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 649
S




[(S)-(4-(N,N-Dimethylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 650
S




[(S)-(4-(N-Isopropyl-N- methylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 651
S




[(S)-(4-(N-Ethyl-N- isopropylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 652
S




[(S)-(4-(N-Isobutyl-N- methylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 653
S




[(S)-(4-(N-Isobutyl-N- ethylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 654
S




[(S)-(4-(N-Methyl-N- Neopentylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 655
S




[(S)-(4-(N-Ethyl-N- Neopentylamino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 656
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 657
S




[(S)-(4-(N-Thiazolidinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 658
S




[(S)-(4-(N-Oxazolidinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 659
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 660
S




[(S)-(4-(N-Morpholino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 661
S




[(S)-(4-(N-Thiomorpholino)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 662
S




[(S)-(4-(N-Piperazinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 663
S




[(S)-(4-(4-Methyl-N-piperazinyl)butylthio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 664
S




[(S)-(4-(4-Ethyl-N-piperazinyl)butylthio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 665
S




[(S)-(4-(4-n-Propyl-N-piperazinyl)butylthio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 666
S




[(S)-(4-(4-Isopropyl-N-piperazinyl) butylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 667
S




[(S)-(4-(4-Isobutyl-N-piperazinyl) butylthio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 668
S




[(S)-(4-(4-Neopentyl-N-piperazinyl) butylthio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 669
S




[(S)-(4-(4-(2-Hydroxyethyl)-N- piperazinyl)butylthio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 670
S




[(S)-(4-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 671
S




[(S)-(4-(4-(3-Hydroxy-3- dimethylbutyl)-N-piperazinyl)butylthio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 672
S




[(S)-(4-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 673
S




[(S)-(4-(4-(2-Methoxyethyl)-N- piperazinyl)butylthio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 674
S




[(S)-(4-(4-(2-Methoxy-2-methylproyl)-N- piperazinyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 675
S




[(S)-(4-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 676
S




[(S)-(4-(4-(4-Methoxy-4-methylpentyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 677
S




[(S)-(4-Carboxybutylthio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 678
S




[(S)-(4-Carboxybutylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


 679
S




[(S)-(4-Carboxybutylthio)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]- 4-cyclosporin-sodium salt


 


 680
S




[(S)-(4-Ethoxycarbonylbutylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 681
S




[(S)-(4-isoButoxycarbonylbutylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 682
S




[(S)-(5-Methoxypentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 683
S




[(S)-(4-Carboxypentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 684
S




[(S)-(4-Carboxypentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- potassium salt


 


 685
S




[(S)-(4-Carboxypentylthio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


 686
S




[(S)-(4-Ethoxycarbonylpentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 687
S




[(S)-(4,4′-Di(carboxy)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 688
S




[(S)-(4,4′-Di(carboxy)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- dipotassium salt


 


 689
S




[(S)-(4,4′-Di(carboxy)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- dipotassium salt


 


 690
S




[(S)-(4,4′-Di(ethoxycarbonyl)butylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 691
S




[(S)-(6,6′-Di(carboxy)hexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 692
S




[(S)-(6,6′-Di(carboxy)hexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- dipotassium salt


 


 693
S




[(S)-(6,6′-Di(carboxy)hexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- disodium salt


 


 694
S




[(S)-(6,6′-Di(ethoxycarbonyl) hexylthio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 695
S




[(S)-(7,7′-Di(carboxy)heptylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 696
S




[(S)-(7,7′-Di(carboxy)heptylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- dipotassium salt


 


 697
S




[(S)-((7,7′-Dicarboxy)heptylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin-disodium salt


 


 698
S




[(S)-(7,7′-Di(ethoxycarbonyl)heptylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 699
S




[(S)-(((R)-3-Hydroxymethyl-6-methoxy-6- oxohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 700
S




[(S)-(((S)-3-Hydroxy-6-methoxy-6- oxohexyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 701
S




[(S)-(((R)-3-Hydroxy-6-ethoxy-6- oxohexyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 702
S




[(S)-(((S)-3-Hydroxy-6-ethoxy- 6-oxohexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 703
S




[(S)-(((R)-3-Hydroxy-6- (neopentylamino)hexyl)thio)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 704
S




[(S)-(((S)-3-Hydroxy-6-(neopentylamino) hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 705
S




[(S)-(((R)-3-Hydroxymethyl-6-(imidazol-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 706
S




[(S)-(((S)-3-Hydroxymethyl-6-(imidazo-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 707
S




[(S)-(((R)-3-Hydroxymethyl- 6-morpholinohexyl) thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 708
S




[(S)-(((S)-3-Hydroxymethyl-6- morpholinohexyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 709
S




[(S)-(((R)-3-Hydroxymethyl-6- thiomorpholinohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 710
S




[(S)-(((S)-3-Hydroxymethyl-6- thiomorpholinohexyl)thio)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 711
S




[(S)-(((R)-3-Hydroxymethyl-6-piperazin-1- ylhexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 712
S




[(S)-(((S)-3-Hydroxymethyl-6-piperazin-1- ylhexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 713
S




[(S)-(((R)-3-Hydroxymethyl-6- (4-methylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 714
S




[(S)-(((S)-3-Hydroxymethyl-6- (4-methylpiperazin-1-yl)hexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 715
S




[(S)-(((R)-3-Hydroxymethyl-6- (4-ethylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 716
S




[(S)-(((S)-3-Hydroxymethyl-6- (4-isopropylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 717
S




[(S)-(((R)-3-Hydroxymethyl-6- (4-isopropylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]- 4-cyclosporin


 


 718
S




[(S)-(((S)-3-Hydroxymethyl-6- (4-ethylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 719
S




[(S)-((S)-3-Hydroxymethyl-4- ethoxycarbonylbutylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 720
S




[(S)-((R)-3-Hydroxymethyl-4-ethoxy- carbonylbutylthio)methyl-Sar]-3-cyclosporin


 


 721
S




[(S)-(((S)-4-Hydroxy-7- methoxy-7-oxoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 722
S




[(S)-(((R)-4-Hydroxy-7-methoxy- 7-oxoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 723
S




[(S)-(((S)-4-Hydroxy-7-ethoxy-7-oxoheptyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 724
S




[(S)-(((R)-4-Hydroxy-7-ethoxy-7-oxoheptyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 725
S




[(S)-(((S)-4-Hydroxy-7- (neopentylamino)heptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 726
S




[(S)-(((R)-4-Hydroxy-7- (neopentylamino)heptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 727
S




[(S)-(((S)-4-Hydroxy-7- (imidazol-1-yl)heptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 728
S




[(S)-(((R)-4-Hydroxy-7-(imidazo- 1-yl)heptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 729
S




[(S)-(((S)-4-Hydroxy-7- morpholinoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 730
S 




[(S)-(((R)-4-Hydroxy-7- morpholinoheptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 731
S




[(S)-(((S)-4-Hydroxy-7- thiomorpholinoheptyl) thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 732
S




[(S)-(((R)-4-Hydroxy-7- thiomorpholinoheptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 733
S




[(S)-(((S)-4-Hydroxy-7-piperazin-1-ylheptyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 734
S




[(S)-(((R)-4-Hydroxy-7- piperazin-1-ylheptyl) thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 735
S




[(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 736
S




[(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 737
S




[(S)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 738
S




[(S)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 739
S




[(S)-(((S)-4-Hydroxy-7-(4- isopropylpiperazin-1-yl)heptyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 740
S




[(S)-(((R)-4-Hydroxy-7-(4- isopropylpiperazin-1-yl)heptyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]- 4-cyclosporin


 


 741
S




[(S)-(6-Methoxyhexylthio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 742
S




[(S)-[(N-(2-Aminoethyl) carbamoyl)methylthio]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 743
S




[(S)-[(N-(2-(Neopentylamino)ethyl) carbamoyl)methylthio]Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 744
S




[(S)-[(N-(3-Aminopropyl) carbamoyl)methylthio] methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 745
S




[(S)-[(N-(3-(Neopentylamino)propyl) carbamoyl)methylthio]methyl-Sar]-3- cyclosporin


 


 746
S




[(S)-[(N-(4-Aminobutyl)carbamoyl) methylthio]methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 747
S




[(S)-[(N-(4-(Neopentylamino)butyl) carbamoyl)methylthio]-methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 748
S




[(S)-[(N-(5-Aminopentyl)carbamoyl) methylthio]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 749
S




[(S)-[(N-(5-(Neopentylamino)pentyl) carbamoyl)methylthio]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 750
S




[(S)-[(N-(6-Aminohexyl)carbamoyl) methylthio]methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 751
S




[(S)-[(N-(6-Neopentylamino)hexyl) carbamoyl)methylthio]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 752
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl) methylthio]methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 753
S




[(S)-[([HO-Gly-(D-Glu)6)]carbamoyl) ethylthio]methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 754
S




[(S)-[([HO-Gly-(D-Glu)6) ]carbamoyl) propylthio]methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 755
S




[(S)-((2-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]ethyl)sulfanyl)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 756
S




[(S)-((3-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]propyl)sulfanyl)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 757
S




[(S)-((4-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]butyl) sulfanyl)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 758
S




[(S)-((5-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]pentyl)sulfanyl)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 759
S




[(S)-((6-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]hexyl)sulfanyl)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 760
S




[(S)-(Isopentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 761
S




[(S)-(5-n-Pentylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 762
S




[(S)-(6-n-Hexylthio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 763
S




[(S)-(7-n-Heptylthio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 764
O




[(R)-(Carboxymethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 765
O




[(R)-(Carboxymethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 766
O




[(R)-(Carboxymethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- potassium salt


 


 767
O




[(R)-(2-Hydroxy-2,2-dimethylethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- sodium salt


 


 768
O




[(R)-(2-Methoxyethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 769
O




[(R)-(2-Methoxy-2-methylpropoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 770
O




[(R)-(2-(N-Isopropylamino)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 771
O




[(R)-(2-(N-Isopropyl-N-methylamino) ethoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 772
O




[(R)-(2-(N-Ethyl-N-isopropylamino) ethoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 773
O




[(R)-(2-(N-Isobutylamino)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 774
O




[(R)-(2-(N-Isobutyl-N-methylamino)ethoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 775
O




[(R)-(2-(N-Isobutyl-N-ethylamino)ethoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 776
O




[(R)-(2-(N-Neopentylamino)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 777
O




[(R)-(2-(N-Methyl-N-neopentylamino) ethoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 778
O




[(R)-(2-(N-Ethyl-N-neopentylamino)ethoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 779
O




[(R)-(2-(N-Thiazolidinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 780
O




[(R)-(2-(N-Oxazolidinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 781
O




[(R)-(2-(N-Thiomorpholino)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 782
O




[(R)-(2-(N-Piperazinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 783
O




[(R)-(2-(4-Methyl-N-piperazinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 784
O




[(R)-(2-(4-Ethyl-N-piperazinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 785
O




[(R)-(2-(4-n-Propyl-N-piperazinyl) ethoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 786
O




[(R)-(2-(4-Isopropyl-N- piperazinyl)ethoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 787
O




[(R)-(2-(4-Isobutyl-N- piperazinyl)ethoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 788
O




[(R)-(2-(4-Neopentyl-N- piperazinyl)ethoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 789
O




[(R)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 790
O




[(R)-(2-(4-(2-Hydroxy-2- methylpropyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 791
O




[(R)-(2-(4-(3-Hydroxy-3- methylbutyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 792
O




[(R)-(2-(4-(4-Hydroxy-4- methylpentyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 793
O




[(R)-(2-(4-(2-Methoxyethyl)-N- piperazinyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 794
O




[(R)-(2-(4-(2-Methoxy-2- methylpropyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 795
O




[(R)-(2-(4-(3-Methoxy-3- methylbutyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 796
O




[(R)-(2-(4-(4-Methoxy-4- methylpentyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 797
O




[(R)-(2-Carboxyethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 798
O




[(R)-(2-Carboxyethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 799
O




[(R)-(2-(Ethoxycarbonyl)ethoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 800
O




[(R)-(3-Hydroxy-3-methylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 801
O




[(R)-(3-Methoxypropoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 802
O




[(R)-(3-Methoxy-3-methylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 803
O




[(R)-(3-(N-Isopropylamino)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 804
O




[(R)-(3-(N-Isopropyl-N-methylamino) propoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 805
O




[(R)-(3-(N-Ethyl-N-isopropylamino) propoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 806
O




[(R)-(3-(N-Isobutylamino)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 807
O




[(R)-(3-N-Isobutyl-N-methylamino) propoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 808
O




[(R)-(3-(N-Isobutyl-N-ethylamino) propoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 809
O




[(R)-(3-(N,N-Diisobutylamino)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 810
O




[(R)-3-(N-Neopentylamino)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 811
O




[(R)-(3-(N-Methyl-N-Neopentylamino) propoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 812
O




[(R)-(3-(N-Ethyl-N-Neopentylamino) propoxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 813
O




[(R)-(3-(N-Thiazolidinyl)propoxymethyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 814
O




[(R)-(3-(N-Oxazolidinyl)propoxymethyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 815
O




[(R)-(3-(N-Thiomorpholino)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 816
O




[(R)-(3-(N-Piperazinyl)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 817
O




[(R)-(3-(4-Methyl-N-piperazinyl) propoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 818
O




[(R)-(3-(4-Ethyl-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 819
O




[(R)-(3-(4-Propyl-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 820
O




[(R)-(3-(4-Isopropyl-N- piperazinyl)propoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 821
O




[(R)-(3-(4-Isobutyl-N- piperazinyl)propoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 822
O




[(R)-(3-(4-Neopentyl-N- piperazinyl)propoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 823
O




[(R)-(3-(4-(2-Hydroxyethyl)-N- piperazinyl)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 824
O




[(R)-(3-(4-(2-Hydroxy-2,2-dimethylethyl)-N- piperazinyl)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 825
O




[(R)-(3-(4-(3-Hydroxy-3,3- dimethylpropyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 826
O




[(R)-(3-(4-(4-Hydroxy-4,4- dimethylbutyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 827
O




[(R)-(3-(4-(2-Methoxyethyl)-N- piperazinyl)propoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 828
O




[(R)-(3-(4-(2-Methoxy-2- methylpropyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 829
O




[(R)-(3-(4-(3-Methoxy-3- methylbutyl)-N-piperazinyl)propoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 830
O




[(R)-(3-(4-(4-Methoxy-4- methylpentyl)-N-piperazinyl)propoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 831
O




[(R)-(3-Carboxypropoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 832
O




[(R)-(3-Carboxypropoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


 833
O




[(R)-(3-Carboxypropoxy)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- sodium salt


 


 834
O




[(R)-(3-(Ethoxycarbonyl)propoxy)methyl-Sar]- 3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 835
O




[(R)-(4-Hydroxy-4,4-dimethylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 836
O




[(R)-((5-Hydroxy-2-methylpentan- 2-yl)oxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 837
O




[(R)-(4-Hydroxy-2,2-dimethylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 838
O




[(R)-(4-Hydroxy-3,3-dimethylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 839
O




[(R)-(4-Methoxy-4-methylpentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 840
O




[(R)-(3-(1-Hydroxycyclopropyl)propoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 841
O




[(R)-((2-(1-(Hydroxymethyl) cyclopropyl)ethoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 842
O




[(R)-(((1-(2-Hydroxyethyl)cyclopropyl)methyl)- oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 843
O




[(R)-((1-(3-Hydroxypropyl) cyclopropyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 844
O




[(R)-((S)-4-Hydroxyhexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 845
O




[(R)-((R)-4-Hydroxyhexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 846
O




[(R)-(((S)-3-(Hydroxymethyl)pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 847
O




[(R)-(((R)-3-(Hydroxymethyl)pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 848
O




[(R)-((S)-2-Ethyl-4-hydroxybutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 849
O




[(R)-(((R)-2-Ethyl-4-hydroxybutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 850
O




[(R)-(((S)-4,5-Dihydroxy-pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 851
O




[(R)-(((R)-4,5-Dihydroxy-pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 852
O




[(R)-(((S)-4,5-Dihydroxy-4- methylpentyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 853
O




[(R)-(((R)-4,5-Dihydroxy-4- methylpentyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 854
O




[(R)-(((R)-4,6-Dihydroxyhexyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 855
O




[(R)-(((S)-4,6-Dihydroxyhexyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 856
O




[(R)-(((R)-5-Hydroxy-3- (hydroxymethyl)pentyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 857
O




[(R)-(((S)-5-Hydroxy-3- (hydroxymethyl)pentyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 858
O




[(R)-(4-Hydroxy-2-(2-hydroxyethyl)butoxy) methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 859
O




[(R)-((4-(Hydroxymethyl)pent-4-en-1-yl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 860
O




[(R)-((5-Hydroxy-3-methylenepentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 861
O




[(R)-((5-Hydroxy-2-methylenepentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 862
O




[(R)-(2-(2-(Hydroxymethyl)oxiran-2-yl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 863
O




[(R)-((2-(2-Hydroxyethyl)oxiran-2-yl) methoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 864
O




[(R)-(3-(3-Hydroxyoxetan-3-yl) propoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 865
O




[(R)-((4,5-Dihydroxy-4-(hydroxymethyl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 866
O




[(R)-(3-(2-(Hydroxymethyl)oxiran-2-yl) propoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 867
O




[(R)-(2-(2-(2-Hydroxyethyl)oxiran-2-yl) ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 868
O




[(R)-((2-(3-Hydroxypropyl)oxiran-2-yl) methoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 869
O




[(R)-((5-Hydroxy-4-oxohexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 870
O




[(R)-((6-Hydroxy-5-oxohexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 871
O




[(R)-((6-Hydroxy-5-oxohexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 872
O




[(R)-(((R)-4-Hydroxy-5-(pyrrolidin-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 873
O




[(R)-(((S)-4-Hydroxy-5-(pyrrolidin-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 874
O




[(R)-(((R)-4-Hydroxy-6-(pyrrolidin-1-yl) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 875
O




[(R)-(((S)-4-Hydroxy-6-(piperidin-1-yl) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 876
O




[(R)-(((R)-4-Hydroxy-5-(imidazol-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 877
O




[(R)-(((S)-4-Hydroxy-5-(imidazo-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 878
O




[(R)-(((R)-4-Hydroxy-6-(imidazo-1-yl) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 879
O




[(R)-(((S)-4-Hydroxy-6-(imidazo-1-yl) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 880
O




[(R)-((R)-3-Hydroxymethyl-4-(imidazol- 1-yl)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 881
O




[(R)-((S)-3-Hydroxymethyl-4-(imidazo- 1-yl)butyoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 882
O




[(R)-(((R)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 883
O




[(R)-(((S)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 884
O




[(R)-(((R)-4-Hydroxy-5-(piperidin-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 885
O




[(R)-(((S)-4-Hydroxy-5-(piperidin-1-yl) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 886
O




[(R)-(((R)-4-Hydroxy-5-(piperidin- 1-yl)hexyl)oxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 887
O




[(R)-(((S)-4-Hydroxy-5-(piperidin-1-yl) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 888
O




[(R)-(((R)-4-Hydroxy-6-morpholinohexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 889
O




[(R)-(((S)-4-Hydroxy-6-morpholinohexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 890
O




[(R)-((R)-2-(Hydroxymethyl)-4- morpholinobutoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 891
O




[(R)-((S)-2-(Hydroxymethyl)-4- morpholinobutoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 892
O




[(R)-((S)-4-Hydroxy-2-(2-morpholinoethyl) butoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 893
O




[(R)-((R)-4-Hydroxy-2-(2-morpholinoethyl) butoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 894
O




[(R)-(((S)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 895
O




[(R)-(((R)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 896
O




[(R)-(((S)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 897
O




[(R)-(((R)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 898
O




[(R)-(((R)-4-Hydroxy-6- (4-isopropylpiperazin-1-yl)hexyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 899
O




[(R)-(((S)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 900
O




[(R)-(((S)-3-Hydroxymethyl- 5-(4-methylpiperazin-1-yl)pentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 901
O




[(R)-(((R)-3-Hydroxymethyl- 5-(4-methylpiperazin-1-yl)pentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 902
O




[(R)-(((S)-3-Hydroxymethyl-5- (4-ethylpiperazin-1-yl)pentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 903
O




[(R)-(((R)-3-Hydroxymethyl-5-(4- ethylpiperazin-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 904
O




[(R)-(((R)-3-Hydroxymethyl-5- (4-isopropylpiperazin-1-yl)pentyl) oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 905
O




[(R)-(((S)-3-Hydroxymethyl-5-(4- isopropylpiperazin-1-yl)pentyl)oxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 906
O




[(R)-(((R)-4-Hydroxy-5-(neopentylamino) pentyl)oxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 907
O




[(R)-(((S)-4-Hydroxy-5-(neopentylamino) pentyl)oxy)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 908
O




[(R)-(((S)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)oxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 909
O




[(R)-((R)-4-Hydroxy-3- ((neopentylamino)methyl)butoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 910
O




[(R)-((S)-4-Hydroxy-2- ((neopentylamino)methyl)butoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 911
O




[(R)-((R)-4-Hydroxy-2- ((neopentylamino)methyl)butoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 912
O




[(R)-(((R)-4-Hydroxy-6-(neopentylamino) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 913
O




[(R)-(((S)-4-Hydroxy-6-(neopentylamino) hexyl)oxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 914
O




[(R)-(((R)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)oxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 915
O




[(R)-(((S)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)oxy)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 916
O




[(R)-((R)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 917
O




[(R)-((S)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 918
O




[(R)-(4-(N,N-Dimethylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 919
O




[(R)-(4-(N,N-Diethylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 920
O




[(R)-(4-(N-Isopropylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 921
O




[(R)-(4-(N-Isopropyl-N-methylamino) butoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 922
O




[(R)-(4-(N-Ethyl-N-isopropylamino) butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 923
O




[(R)-(4-(N-Isobutylamino) butoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 924
O




[(R)-(4-(N-Isobutyl-N- methylamino)butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 925
O




[(R)-(4-(N-Isobutyl-N- ethylamino)butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 926
O




[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 927
O




[(R)-(4-(N-Neopentylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 928
O




[(R)-(4-(N-Methyl-N- neopentylamino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 929
O




[(R)-(4-(N-Ethyl-N- neopentylamino)butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 930
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 931
O




[(R)-(4-(N-Thiazolidinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 932
O




[(R)-(4-(N-Oxazolidinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 933
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 934
O




[(R)-(4-(N-Morpholino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 935
O




[(R)-(4-(N-Thiomorpholino)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 936
O




[(R)-(4-(N-Piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 937
O




[(R)-(4-(4-Methyl-N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 938
O




[(R)-(4-(4-Ethyl-N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 939
O




[(R)-(4-(4-n-Propyl-N- piperazinyl)butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 940
O




[(R)-(4-(4-Isopropyl-N- piperazinyl)butoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 941
O




[(R)-(4-(4-Isobutyl-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 942
O




[(R)-(4-(4-Neopentyl-N- piperazinyl)butoxy)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 943
O




[(R)-(4-(4-(2-Hydroxymethyl)-N- piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 944
O




[(R)-(4-(4-(2-Hydroxy-2-methylpropyl)- N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 945
O




[(R)-(4-(4-(3-Hydroxy-3- methylbutyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 946
O




[(R)-(4-(4-(4-Hydroxy-4,4- dimethylbutyl)-N-piperazinyl)butoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 947
O




[(R)-(4-(4-(2-Methoxyethyl)- N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 948
O




[(R)-(4-(4-(2-Methoxy-2-methylpropyl)- N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 949
O




[(R)-(4-(4-(3-Methoxy-3-methylbutyl)- N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 950
O




[(R)-(4-(4-(4-methoxy-4-methylpentyl)-N- piperazinyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 951
O




[(R)-(4-Carboxybutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 952
O




[(R)-(4-Carboxybutoxy)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


 953
O




[(R)-(4-Carboxybutoxy)methyl- Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


 954
O




[(R)-(4-(Ethoxycarbonyl)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 955
O




[(R)-(5-Carboxypentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 956
O




[(R)-(5-Carboxypentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- potassium salt


 


 957
O




[(R)-(5-Carboxypentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- sodium salt


 


 958
O




[(R)-(5-(Ethoxycarbonyl)pentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 959
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 960
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 961
O




[(R)-(6,6′-Di(carboxy)hexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 962
O




[(R)-(6,6′-Di(carboxy)hexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin-dipotassium salt


 


 963
O




[(R)-(6,6′-Di(carboxy)hexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- disodium salt


 


 964
O




[(R)-(6,6′-Di(ethoxycarbonyl)hexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 965
O




[(R)-(7,7′-Di(carboxy)heptyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 966
O




[(R)-(7,7′-Di(carboxy)heptyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- dipotassium salt


 


 967
O




[(R)-(7,7′-Di(carboxy)heptyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin- disodium salt


 


 968
O




[(R)-(7,7′-Di(ethoxycarbonyl)heptyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 969
O




[(R)-(((R)-3-Hydroxymethyl-6-methoxy-6- oxohexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 970
O




[(R)-(((S)-3-Hydroxy-6-methoxy- 6-oxohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 971
O




[(R)-(((R)-3-Hydroxy-6-ethoxy- 6-oxohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 972
O




[(R)-(((S)-3-Hydroxy-6-ethoxy-6- oxohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 973
O




[(R)-(((R)-3-Hydroxy-6-(neopentylamino) hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 974
O




[(R)-(((S)-3-Hydroxy-6-(neopentylamino) hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


 975
O




[(R)-(((R)-3-Hydroxymethyl-6-(imidazol-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 976
O




[(R)-(((S)-3-Hydroxymethyl-6-(imidazo-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 977
O




[(R)-(((R)-3-Hydroxymethyl-6-morpholinohexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 978
O




[(R)-(((S)-3-Hydroxymethyl-6-morpholinohexyl) thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 979
O




[(R)-(((R)-3-Hydroxymethyl-6- thiomorpholinohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 980
O




[(R)-(((S)-3-Hydroxymethyl-6- thiomorpholinohexyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 981
O




[(R)-(((R)-3-Hydroxymethyl-6-piperazin-1- ylhexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 982
O




[(R)-(((S)-3-Hydroxymethyl-6-piperazin-1- ylhexyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 983
O




[(R)-(((R)-3-Hydroxymethyl- 6-(4-methylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 984
O




[(R)-(((S)-3-Hydroxymethyl-6-(4- methylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 985
O




[(R)-(((R)-3-Hydroxymethyl-6-(4- ethylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4- cyclosporin


 


 986
O




[(R)-(((S)-3-Hydroxymethyl-6-(4- isopropylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 987
O




[(R)-(((R)-3-Hydroxymethyl-6-(4- isopropylpiperazin-1-yl)hexyl)thio) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


 988
O




[(R)-(((S)-3-Hydroxymethyl-6-(4- ethylpiperazin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 989
O




[(R)-((R)-3-Hydroxymethyl-4- ethoxycarbonylbutyoxy)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 990
O




[(R)-((S)-3-Hydroxymethyl-4- ethoxycarbonylbutoxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 991
O




[(R)-(((R)-4-Hydroxy-7-methoxy-7- oxoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 992
O




[(R)-(((S)-4-Hydroxy-7-methoxy-7- oxoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 993
O




[(R)-(((R)-4-Hydroxy-7-ethoxy-7- oxoheptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 994
O




[(R)-(((S)-4-Hydroxy-7-ethoxy-7- oxoheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


 995
O




[(R)-(((S)-4-Hydroxy-7- (neopentylamino)heptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 996
O




[(R)-(((R)-4-Hydroxy-7- (neopentylamino)heptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 997
O




[(R)-(((S)-4-Hydroxy-7- (imidazol-1-yl)heptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 998
O




[(R)-(((R)-4-Hydroxy-7-(imidazo- 1-yl)heptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


 999
O




[(R)-(((S)-4-Hydroxy-7- morpholinoheptyl)thio)methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1000
O




[(R)-(((R)-4-Hydroxy-7- morpholinoheptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1001
O




[(R)-(((S)-4-Hydroxy-7- thiomorpholinoheptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1002
O




[(R)-(((R)-4-Hydroxy-7- thiomorpholinoheptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1003
O




[(R)-(((S)-4-Hydroxy-7-piperazin- 1-ylheptyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1004
O




[(R)-(((R)-4-Hydroxy-7-piperazin- 1-ylheptyl)thio)methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


1005
O




[(R)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1006
O




[(R)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1007
O




[(R)-(((S)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1008
O




[(R)-(((R)-4-Hydroxy-7-(4-ethylpiperazin-1-yl) heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1009
O




[(R)-(((S)-4-Hydroxy-7-(4-isopropylpiperazin- 1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


1010
O




[(R)-(((R)-4-Hydroxy-7-(4-isopropylpiperazin- 1-yl)heptyl)thio)methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


1011
O




[(R)-(5-Methoxypentyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1012
O




[(R)-(6-Hydroxyhexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1013
O




[(R)-(6-Methoxyhexyloxy)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1014
O




[(R)-[(N-(2-Aminoethyl) carbamoyl)methoxy]methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


1015
O




[(R)-[(N-(2-(Neopentylamino)ethyl) carbamoyl)methoxy] methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1016
O




[(R)-[(N-(3-Aminopropyl)carbamoyl) methoxy]methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


1017
O




[(R)-[(N-(3-(Neopentylamino) propyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1018
O




[(R)-[(N-(4-Aminobutyl) carbamoyl)methoxy]methyl-Sar]-3-[(γ- hydroxy)-N-MeLeu]-4-cyclosporin


 


1019
O




[(R)-[(N-(4-(Neopentylamino) butyl)carbamoyl)methoxy]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1020
O




[(R)-[(N-(5-Aminopentyl) carbamoyl)methoxy]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1021
O




[(R)-[(N-(5-(Neopentylamino)pentyl) carbamoyl)methoxy]methyl-Sar]-3- cyclosporin


 


1022
O




[(R)-[(N-(6-Aminohexyl)carbamoyl) methoxy]methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


1023
O




[(R)-[(N-(6-(Neopentylamino)hexyl) carbamoyl)methoxy] methyl-Sar]-3-cyclosporin


 


1024
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl) methoxy]methyl-Sar]-3-[(γ-hydroxy)- N-MeLeu]-4-cyclosporin


 


1025
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl)ethoxy] methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1026
O




[(R)-[([HO-Gly-(D-Glu)6] carbamoyl)propoxy]methyl-Sar]-3- [(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1027
O




[(R)-((2-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]ethoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1028
O




[(R)-((3-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]propoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1029
O




[(R)-((4-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]butoxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1030
O




[(R)-((5-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]pentyloxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1031
O




[(R)-((6-[([HO-Gly-(D-Glu)6] carbamoyl)methoxy]hexyloxy) methyl-Sar]-3-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1032
O




[(R)-(4-Butoxy)methyl-Sar]-3- [(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1033
O




[(R)-(5-Pentyloxy)methyl-Sar]-3- [(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1034
O




[(R)-(6-Hexyloxy)methyl-Sar]-3- [(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1035
O




[(R)-(7-Heptyloxy)methyl-Sar]-3- [(γ-hydroxy)-N- MeLeu]-4-cyclosporin


 


1036
CH2
—CH2N(CH3)2
[(R)-2-(N,N-Dimethylamino)propyl-Sar]-3- [(γ-hydroxy)-N- MeLeu]-4-cyclosporin
















TABLE 3













 










Ex. 





No.
W
Ra
Name





1037
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1038
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1039
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1040
S




[(S)-(Ethoxycarbonylmethylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1041
S




[(S)-(tert-butoxycarbonylmethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1042
S




[(S)-(2-Hydroxyethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1043
S




[(S)-(2-Hydroxy-2-methylpropylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1044
S




[(S)-(2-Methoxyethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1045
S




[(S)-(2-Methoxy-2-methylpropylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1046
S




[(S)-(2-(N-Isopropylamino)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1047
S




[(S)-(2-(N-Isopropyl-N-methylamino)ethylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1048
S




[(S)-(2-(N-Isopropyl-N-ethylamino)ethylthio)methyl-Sar]-3 [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1049
S




[(S)-(2-(N-Isobutylamino)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1050
S




[(S)-(2-(N-Isobutyl-N-methylamino)ethylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1051
S




[(S)-(2-(N-Isobutyl-N-ethylamino)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1052
S




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1053
S




[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1054
S




[(S)-(2-(N-Ethyl-N-neopentylamino)ethylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1055
S




[(S)-(2-(N-Thiazolidinyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1056
S




[(S)-(2-(N-Oxazolidinyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1057
S




[(S)-(2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1058
S




[(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1059
S




[(S)-(2-(N-Piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1060
S




[(S)-(2-(4-Methyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1061
S




[(S)-(2-(4-Ethyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1062
S




[(S)-(2-(4-Propyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1063
S




[(S)-(2-(4-Isopropyl-N-piperazinyl)ethylthio)methyl-Sar-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1064
S




[(S)-(2-(4-Isobutyl-N-piperazinyl)ethylthio)methyl-Sar-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1065
S




[(S)-(2-(4-Neopentyl-N-piperazinyl)ethylthio)methyl-Sar-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1066
S




[(S)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl)ethylthio)methyl- Sar-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1067
S




[(S)-(2-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1068
S




[(S)-(2-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1069
S




[(S)-(2-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1070
S




[(R)-(2-(4-(2-Methoxyethyl)-N-piperazinyl)ethylthio)methyl- Sar-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1071
S




[(S)-(2-(4-(2-Methoxy-2-methylproyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1072
S




[(S)-(2-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1073
S




[(S)-(2-(4-(4-methoxy-4-methylpentyl)-N- piperazinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1074
S




[(S)-(2-Carboxyethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1075
S




[(S)-(2-Carboxyethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1076
S




[(S)-(2-Carboxyethylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1077
S




[(S)-(2-(Ethoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1078
S




[(S)-(2-(isoButoxycarbonyl)ethylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1079
S




[(S)-(3-Hydroxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1080
S




[(S)-(3-Hydroxy-3-methylbutylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1081
S




[(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1082
S




[(S)-(3-Methoxy-3-methylbutylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1083
S




[(S)-(3-(N-Isopropylamino)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1084
S




[(S)-(3-(N-Isopropyl-N-methylamino)propylthio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1085
S




[(S)-(3-(N-Ethyl-N-isopropylamino)propylthio)methyl [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1086
S




[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1087
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1088
S




[(S)-(3-(N-Isobutyl-N-ethylamino)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1089
S




[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1090
S




[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1091
S




[(S)-(3-(N-Methyl-N-neopentylamino)propylthio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1092
S




[(S)-(3-(N-Ethyl-N-neopentylamino)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1093
S




[(S)-(3-(N-Thiazolidinyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-NMeLeu]-4-cyclosporin


 


1094
S




[(S)-(3-(N-Oxazolidinyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-NMeLeu]-4-cyclosporin


 


1095
S




[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1096
S




[(S)-(3-(N-Piperazinyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1097
S




[(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1098
S




[(S)-(3-(4-Ethyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1099
S




[(S)-(3-(4-n-Propyl-N-piperazinyl)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1100
S




[(S)-(3-(4-Isopropyl-N-piperazinyl)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1101
S




[(S)-(3-(4-Isobutyl-N-piperazinyl)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1102
S




[(S)-(3-(4-Neopentyl-N-piperazinyl)propylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1103
S




[(S)-(3-(4-(2-Hydroxyethyl)-N-piperazinyl)propylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1104
S




[(S)-(3-(4-(2-Hydroxy-2-dimethylpropyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1105
S




[(S)-(3-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1106
S




[(S)-(3-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1107
S




[(S)-(3-(4-(2-Methoxyethyl)-N-piperazinyl)propylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1108
S




[(S)-(3-(4-(2-Methoxy-2-methylpropyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1109
S




[(S)-(3-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1110
S




[(S)-(3-(4-(4-Methoxy-4-methylpentyl)-N- piperazinyl)propylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1111
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1112
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1113
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1114
S




[(S)-(3-Methoxycarbonylpropylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1115
S




[(S)-(3-Ethoxycarbonylpropylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1116
S




[(S)-(3-Isobutoxycarbonylpropylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1117
S




[(S)-(4-Hydroxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1118
S




[(S)-(4-Hydroxy-4-methylpentylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1119
S




[(S)-((5-Hydroxy-2-methylpentan-2-yl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1120
S




[(S)-((4-Hydroxy-2,2-dimethylbutyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1121
S




[(S)-((4-Hydroxy-3,3-dimethylbutyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1122
S




[(S)-(3-(1-Hydroxycyclopropyl)propylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1123
S




[(S)-(((2-(1-(Hydroxymethyl)cyclopropyl)ethyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1124
S




[(S)-(((1-(2-Hydroxyethyl)cyclopropyl)methyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1125
S




[(S)-((1-(3-Hydroxypropyl)cyclopropyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1126
S




[(S)-((S)-4-Hydroxyhexylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin 


 


1127
S




[(S)-((R)-4-Hydroxyhexylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1128
S




[(S)-(((S)-3-(Hydroxymethyl)pentyl)thio)methyl-Sar]- -[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1129
S




[(S)-(((R)-3-(Hydroxymethyl)pentyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1130
S




[(S)-(((S)-2-Ethyl-4-hydroxybutyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1131
S




[(S)-(((R)-2-Ethyl-4-hydroxybutyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1132
S




[(S)-(((S)-4,5-Dihydroxy-4-pentyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1133
S




[(S)-(((R)-4,5-Dihydroxy-4-pentyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1134
S




[(S)-(((S)-4,5-Dihydroxy-4-methylpentyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1135
S




[(S)-(((R)-4,5-Dihydroxy-4-methylpentyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1136
S




[(S)-(((R)-4,6-Dihydroxyhexyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1137
S




[(S)-(((S)-4,6-Dihydroxyhexyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1138
S




[(S)-(((R)-5-Hydroxy-3-(hydroxymethyl)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1139
S




[(S)-(((S)-5-Hydroxy-3-(hydroxymethyl)pentyl)thio)methyl- Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin


 


1140
S




[(S)-((4-Hydroxy-2-(2-hydroxyethyl)butyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1141
S




[(S)-((4-(Hydroxymethyl)pent-4-en-1-yl)thio)methyl)-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1142
S




[(S)-((5-Hydroxy-3-methylenepentyl)thio)methyl)-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1143
S




[(S)-((5-Hydroxy-2-methylenepentyl)thio)methyl)-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1144
S




[(S)-((2-(2-(Hydroxymethyl)oxiran-2-yl)ethyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1145
S




[(S)-(((2-(2-Hydroxyethyl)oxiran-2-yl)methyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1146
S




[(S)-((3-(3-Hydroxyoxetan-3-yl)propyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1147
S




[(S)-((4,5-Dihydroxy-4-(hydroxymethyl)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1148
S




[(S)-((3-(2-(Hydroxymethyl)oxiran-2-yl)propyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1149
S




[(S)-((2-(2-(2-Hydroxyethyl)oxiran-2-yl)ethyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1150
S




[(S)-(((2-(3-Hydroxypropyl)oxiran-2-yl)methyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1151
S




[(S)-((5-Hydroxy-4-oxohexyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1152
S




[(S)-((6-Hydroxy-5-oxohexyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1153
S




[(S)-((6-Hydroxy-5-oxohexyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1154
S




[(S)-(((R)-4-Hydroxy-5-(pyrrolidin-1-yl)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1155
S




[(S)-(((S)-4-Hydroxy-5-(pyrrolidin-1-yl)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1156
S




[(S)-(((R)-4-Hydroxy-6-(pyrrolidin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1157
S




[(S)-(((S)-4-Hydroxy-6-(piperidin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1158
S




[(S)-(((R)-4-Hydroxy-5-(imidazol-1-yl)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1159
S




[(S)-(((S)-4-Hydroxy-5-(imidazo-1-yl)pentyl)thio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1160
S




[(S)-(((R)-4-Hydroxy-6-(imidazo-1-yl)hexyl)thio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1161
S




[(S)-(((S)-4-Hydroxy-6-(imidazo-1-yl)hexyl)thio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1162
S




[(S)-(((R)-3-Hydroxymethyl-4-(imidazol-1- yl)butyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1163
S




[(S)-(((S)-3-Hydroxymethyl-4-(imidazo-1- yl)butyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1164
S




[(S)-(((R)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1165
S




[(S)-(((S)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1166
S




[(S)-(((R)-4-Hydroxy-5-(piperidin-1-yl)pentyl)thio)methy- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1167
S




[(S)-(((S)-4-Hydroxy-5-(piperidin-1-yl)pentyl)thio)methy- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1168
S




[(S)-(((R)-4-Hydroxy-5-(piperidin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1169
S




[(S)-(((S)-4-Hydroxy-5-(piperidin-1-yl)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1170
S




[(S)-(((R)-4-Hydroxy-6-morpholinohexyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1171
S




[(S)-(((S)-4-Hydroxy-6-morpholinohexyl)thio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1172
S




[(S)-(((R)-2-(Hydroxymethyl)-4-morpholinobutyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1173
S




[(S)-(((S)-2-(Hydroxymethyl)-4-morpholinobutyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1174
S




[(S)-(((S)-4-Hydroxy-2-(2-morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1175
S




[(S)-(((R)-4-Hydroxy-2-(2-morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1176
S




[(S)-(((S)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1177
S




[(S)-(((R)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1178
S




[(S)-(((S)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1179
S




[(S)-(((R)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1180
S




[(S)-(((R)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1181
S




[(S)-(((S)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1182
S




[(S)-(((R)-2-(Hydroxymethyl)-4-morpholinobutyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1183
S




[(S)-(((S)-3-Hydroxymethyl-5-(4-methylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1184
S




[(S)-(((R)-3-Hydroxymethyl-5-(4-methylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1185
S




[(S)-(((S)-3-Hydroxymethyl-5-(4-ethylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1186
S




[(S)-(((R)-3-Hydroxymethyl-5-(4-ethylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1187
S




[(S)-(((R)-3-Hydroxymethyl-5-(4-isopropylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1188
S




[(S)-(((S)-3-Hydroxymethyl-5-(4-isopropylpiperazin-1- yl)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1189
S




[(S)-(((R)-2-(Hydroxymethyl)-4-morpholinobutyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1190
S




[(S)-(((S)-2-(Hydroxymethyl)-4-morpholinobutyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1191
S




[(S)-(((S)-4-Hydroxy-2-(2-morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1192
S




[(S)-(((R)-4-Hydroxy-2-(2-morpholinoethyl)butyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1193
S




[(S)-(((R)-4-Hydroxy-5-(neopentylamino)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1194
S




[(S)-(((S)-4-Hydroxy-5-(neopentylamino)pentyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1195
S




[(S)-(((S)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1196
S




[(S)-(((R)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1197
S




[(S)-(((S)-4-Hydroxy-2- ((neopentylamino)methyl)butyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1198
S




[(S)-(((R)-4-Hydroxy-2- ((neopentylamino)methyl)butyl)thio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1199
S




[(S)-(((R)-4-Hydroxy-6-(neopentylamino)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1200
S




[(S)-(((S)-4-Hydroxy-6-(neopentylamino)hexyl)thio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1201
S




[(S)-(((R)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1202
S




[(S)-(((S)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)thio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1203
S




[(S)-(((R)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butyl)thio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1204
S




[(S)-(((S)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butyl)thio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1205
S




[(S)-(4-Methoxy-4-methylpentylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1206
S




[(S)-(4-(N,N-Dimethylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1207
S




[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1208
S




[(S)-(4 -(N-Isopropylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1209
S




[(S)-(4-(N-Isopropyl-N-methylamino)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1210
S




[(R)-(4-(N-Ethyl-N-isopropylamino)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1211
S




[(S)-(4-(N-Isobutylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1212
S




[(S)-(4-(N-Isobutyl-N-methylamino)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1213
S




[(S)-(4-(N-Isobutyl-N-ethylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1214
S




[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1215
S




[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1216
S




[(S)-(4-(N-Methyl-N-neopentylamino)butylthio)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1217
S




[(S)-(4-(N-Ethyl-N-neopentylamino)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1218
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1219
S




[(S)-(4-(N-Thiazolidinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1220
S




[(S)-(4-(N-Oxazolidinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1221
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)- NMeLeu]-4-cyclosporin


 


1222
S




[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1223
S




[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1224
S




[(S)-(4-(N-Piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1225
S




[(S)-(4-(4-Methyl-N-piperazinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1226
S




[(S)-(4-(4-Ethyl-N-piperazinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1227
S




[(S)-(4-(4-n-Propyl-N-piperazinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1228
S




[(S)-(4-(4-Isopropyl-N-piperazinyl)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1229
S




[(S)-(4-(4-Isobutyl-N-piperazinyl)butylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1230
S




[(S)-(4-(4-Neopentyl-N-piperazinyl)butylthio)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1231
S




[(S)-(4-(4-(2-Hydroxyethyl)-N-piperazinyl)butylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1232
S




[(S)-(4-(4-(2-Hydroxy-2-methylpropyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1233
S




[(S)-(4-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1234
S




[(S)-(4-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1235
S




[(S)-(4-(4-(2-Methoxyethyl)-N-piperazinyl)butylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1236
S




[(S)-(4-(4-(2-Methoxy-2-methylpropyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1237
S




[(S)-(4-(4-(3-Methoxy-3-methylbutyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1238
S




[(S)-(4-(4-(4-Methoxy-4-methylpentyl)-N- piperazinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1239
S




[(S)-(4-Carboxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1240
S




[(S)-(4-Carboxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1241
S




[(S)-(4-Carboxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1242
S




[(S)-(4-Methoxycarbonylbutylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1243
S




[(S)-(4-Ethoxycarbonylbutylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1244
S




[(S)-(4-isoButoxycarbonylbutylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1245
S




[(S)-(5-Hydroxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1246
S




[(S)-(5-Methoxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1247
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1248
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1249
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1250
S




[(S)-(4-Ethoxycarbonylpentylthio)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1251
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1252
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin-dipotassium salt


 


1253
S




[(S)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1254
S




[(S)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1255
S




[(S)-(6-Hydroxyhexylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1256
S




[(S)-(6-Methoxyhexylthio)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1257
S




[(S)-[(N-(2-Aminoethyl)carbamoyl)methylthio]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1258
S




[(S)-[(N-(2-(Neopentylamino)ethyl)carbamoyl)methylthio] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1259
S




[(S)-[(N-(3-Aminopropyl)carbamoyl)methylthio]methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1260
S




[(S)-[(N-(3-(Neopentylamino)propyl)carbamoyl)methylthio] methyl-Sar]-3-cyclosporin


 


1261
S




[(S)-[(N-(4-Aminobutyl)carbamoyl)methylthio]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1262
S




[(S)-[(N-(4-(Neopentylamino)butyl)carbamoyl)methylthio] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1263
S




[(S)-[(N-(5-Aminopentyl)carbamoyl)methylthio]methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1264
S




[(S)-[(N-(5-(Neopentylamino)pentyl)carbamoyl)methylthio] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1265
S




[(S)-[(N-(6-Aminohexyl)carbamoyl)methylthio]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1266
S




[(S)-[(N-(6-Neopentylamino)hexyl)carbamoyl)methylthio] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1267
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl)methylthio]methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1268
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl)ethylthio]methyl-Sar]- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1269
S




[(S)-[([HO-Gly-(D-Glu)6]carbamoyl)propylthio]methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1270
S




[(S)-((2-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]ethyl) sulfanyl)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1271
S




[(S)-((3-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]propyl) sulfanyl)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1272
S




[(S)-((4-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]butyl) sulfanyl)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1273
S




[(S)-((5-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]pentyl) sulfanyl)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1274
S




[(S)-((6-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]hexyl) sulfanyl)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1275
S




[(S)-(Isopentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1276
S




[(S)-(5-n-Pentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1277
S




[(S)-(6-n-Hexylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1278
S




[(S)-(7-n-Heptylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]- 4-cyclosporin


 


1279
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1280
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1281
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1282
O




[(R)-((Ethoxycarbonyl)methoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1283
O




[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1284
O




[(R)-(2-Hydroxy-2,2-dimethylethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1285
O




[(R)-(2-Methoxyethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1286
O




[(R)-(2-Methoxy-2-methylpropoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1287
O




[(R)-(2-(N-Isopropylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1288
O




[(R)-(2-(N-Isopropyl-N-methylamino)ethoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1289
O




[(R)-(2-(N-Ethyl-N-isopropylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1290
O




[(R)-(2-(N-Isobutylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1291
O




[(R)-(2-(N-Isobuty l-N-methylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1292
O




[(R)-(2-(N-Isobutyl-N-ethylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1293
O




[(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1294
O




[(R)-(2-(N-Methyl-N-neopentylamino)ethoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1295
O




[(R)-(2-(N-Ethyl-N-neopentylamino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1296
O




[(R)-(2-(N-Thiazolidinyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1297
O




[(R)-(2-(N-Oxazolidinyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1298
O




[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1299
O




[(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1300
O




[(R)-(2-(N-Piperazinyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1301
O




[(R)-(2-(4-Methyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1302
O




[(R)-(2-(4-Ethyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1303
O




[(R)-(2-(4-Propyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1304
O




[(R)-(2-(4-Isopropyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1305
O




[(R)-(2-(4-Isobutyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1306
O




[(R)-(2-(4-Neopentyl-N-piperazinyl)ethoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1307
O




[(R)-(2-(4-(2-Hydroxyethyl)-N-piperazinyl)ethoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1308
O




[(R)-(2-(4-(2-Hydroxy-2-methylpropyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1309
O




[(R)-(2-(4-(3-Hydroxy-3-methylbutyl)-N- piperazinyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1310
O




[(R)-(2-(4-(4-Hydroxy-4-methylpentyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1311
O




[(R)-(2-(4-(2-Methoxyethyl)-N-piperazinyl)ethoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1312
O




[(R)-(2-(4-(2-Methoxy-2-methylpropyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1313
O




[(R)-(2-(4-(3-Methoxy-3-methylbutyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1314
O




[(R)-(2-(4-(4-Methoxy-4-methylpentyl)-N-piperazinyl) ethoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1315
O




[(R)-(2-Carboxyethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1316
O




[(R)-(2-Carboxyethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1317
O




[(R)-(2-Carboxyethoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1318
O




[(R)-(2-(Ethoxycarbonyl)ethoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1319
O




[(R)-(3-Hydroxypropoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1320
O




[(R)-(3-Hydroxy-3-methylbutoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1321
O




[(R)-(3-Methoxypropoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1322
O




[(R)-(3-Methoxy-3-methylbutoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1323
O




[(R)-(3-(N-Isopropylamino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1324
O




[(R)-(3-(N-Isopropyl-N-methylamino)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1325
O




[(R)-(3-(N-Ethyl-N-isopropylamino)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1326
O




[(R)-(3-(N-Isobutylamino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1327
O




[(R)-(3-(N-Isobutyl-N-methylamino)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1328
O




[(R)-(3-(N-Ethyl-N-isobutylamino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1329
O




[(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1330
O




[(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1331
O




[(R)-(3-(N-Methyl-N-neopentylamino)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1332
O




[(R)-(3-(N-Ethyl-N-neopentylamino)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1333
O




[(R)-(3-(N-Thiazolidinyl)propoxymethyl-Sar]-3-[(γ-methoxy)- NMeLeu]-4-cyclosporin


 


1334
O




[(R)-(3-(N-Oxazolidinyl)propoxymethyl-Sar]-3-[(γ-methoxy)- NMeLeu]-4-cyclosporin


 


1335
O




[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1336
O




[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1337
O




[(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1338
O




[(R)-(3-(N-Piperazinyl)propoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1339
O




[(R)-(3-(4-Methyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1340
O




[(R)-(3-(4-Ethyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1341
O




[(R)-(3-(4-Propyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1342
O




[(R)-(3-(4-Isopropy1-N-piperazinyl)propoxy)methyl-Sar]-3- [(y-methoxy)-N-MeLeu]-4-cyclosporin


 


1343
O




[(R)-(3-(4-Isobutyl-N-piperazinyl)propoxy)methyl-Sar]-3-[(y- methoxy)-N-MeLeu]-4-cyclosporin


 


1344
O




[(R)-(3-(4-Neopentyl-N-piperazinyl)propoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1345
O




[(R)-(3-(4-(2-Hydroxyethyl)-N-piperazinyl)propoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1346
O




[(R)-(3-(4-(2-Hydroxy-2,2-dimethylethyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1347
O




[(R)-(3-(4-(3-Hydroxy-3,3-dimethylpropyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1348
O




[(R)-(3-(4-(4-Hydroxy-4,4-dimethylbutyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1349
O




[(R)-(3-(4-(2-Methoxyethyl)-N-piperazinyl)propoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1350
O




[(R)-(3-(4-(2-Methoxy-2-methylpropyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1351
O




[(R)-(3-(4-(3-Methoxy-3-methylbutyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1352
O




[(R)-(3-(4-(4-Methoxy-4-methylpentyl)-N-piperazinyl) propoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1353
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1354
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1355
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1356
O




[(R)-(3-(Ethoxycarbonyl)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1357
O




[(R)-(4-Hydroxybutoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1358
O




[(R)-((5-Hydroxy-2-methylpentan-2-yl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1359
O




[(R)-(4-Hydroxy-2,2-dimethylbutoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1360
O




[(R)-(4-Hydroxy-3,3-dimethylbutoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1361
O




[(R)-(4-Hydroxy-4-methylpentyloxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1362
O




[(R)-(4-Methoxybutoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1363
O




[(R)-(4-Methoxy-4-methylpentyloxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1364
O




[(R)-(3-(1-Hydroxycyclopropyl)propoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1365
O




[(R)-((2-(1-(Hydroxymethyl)cyclopropyl)ethoxy)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1366
O




[(R)-(((1-(2-Hydroxyethyl)cyclopropyl)methyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1367
O




[(R)-((1-(3-Hydroxypropyl)cyclopropyl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1368
O




[(R)-((S)-4-Hydroxyhcxyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1369
O




[(R)-((R)-4-Hydroxyhexyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1370
O




[(R)-(((S)-3-(Hydroxymethyl)pentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1371
O




[(R)-(((R)-3-(Hydroxymethyl)pentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1372
O




[(R)-((S)-2-Ethyl-4-hydroxybutoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1373
O




[(R)-(((R)-2-Ethyl-4-hydroxybutoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1374
O




[(R)-(((S)-4,5-Dihydroxy-4-pentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1375
O




[(R)-(((R)-4,5-Dihydroxy-4-pentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin 


 


1376
O




[(R)-(((S)-4,5-Dihydroxy-4-methylpentyl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1377
O




[(R)-(((R)-4,5-Dihydroxy-4-methylpentyl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1378
O




[(R)-(((R)-4,6-Dihydroxyhexyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1379
O




[(R)-(((S)-4,6-Dihydroxyhexyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1380
O




[(R)-(((R)-5-Hydroxy-3-(hydroxymethyl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1381
O




[(R)-(((S)-5-Hydroxy-3-(hydroxymethyl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1382
O




[(R)-(4-Hydroxy-2-(2-hydroxyethyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1383
O




[(R)-((4-(Hydroxymethyl)pent-4-en-1-yl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1384
O




[(R)-((5-Hydroxy-3-methylenepentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1385
O




[(R)-((5-Hydroxy-2-methylenepentyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1386
O




[(R)-(2-(2-(Hydroxymethyl)oxiran-2-yl)ethoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1387
O




[(R)-((2-(2-Hydroxyethyl)oxiran-2-yl)methoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1388
O




[(R)-(3-(3-Hydroxyoxetan-3-yl)propoxy)methyl-Sar]-3-[(y- methoxy)-N-MeLeu]-4-cyclosporin


 


1389
O




[(R)-((4,5-Dihydroxy-4-(hydroxymethyl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1390
O




[(R)-(3-(2-(Hydroxymethyl)oxiran-2-yl)propoxy)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1391
O




[(R)-(2-(2-(2-Hydroxyethyl)oxiran-2-yl)ethoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1392
O




[(R)-((2-(3-Hydroxypropyl)oxiran-2-yl)methoxy)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1393
O




[(R)-((5-Hydroxy-4-oxohexyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1394
O




[(R)-((6-Hydroxy-5-oxohexyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1395
O




[(R)-((6-Hydroxy-5-oxohexyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1396
O




[(R)-(((R)-4-Hydroxy-5-(pyrrolidin-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1397
O




[(R)-(((S)-4-Hydroxy-5-(pyrrolidin-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1398
O




[(R)-(((R)-4-Hydroxy-6-(pyrrolidin-1-yl)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1399
O




[(R)-(((S)-4-Hydroxy-6-(piperidin-1-yl)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1400
O




[(R)-(((R)-4-Hydroxy-5-(imidazol-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1401
O




[(R)-(((S)-4-Hydroxy-5-(imidazo-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1402
O




[(R)-(((R)-4-Hydroxy-6-(imidazo-1-yl)hexyl)oxy)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1403
O




[(R)-(((S)-4-Hydroxy-6-(imidazo-1-yl)hexyl)oxy)methyl-Sar]- 3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1404
O




[(R)-((R)-3-Hydroxymethyl-4-(imidazol-1-yl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1405
O




[(R)-((S)-3-Hydroxymethyl-4-(imidazo-1-yl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1406
O




[(R)-(((R)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1407
O




[(R)-(((S)-3-Hydroxymethyl-5-(imidazo-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1408
O




[(R)-(((R)-4-Hydroxy-5-(piperidin-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1409
O




[(R)-(((S)-4-Hydroxy-5-(piperidin-1-yl)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1410
O




[(R)-(((R)-4-Hydroxy-5-(piperidin-1-yl)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1411
O




[(R)-(((S)-4-Hydroxy-5-(piperidin-1-yl)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1412
O




[(R)-(((R)-4-Hydroxy-6-morpholinohexyl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1413
O




[(R)-(((S)-4-Hydroxy-6-morpholinohexyl)oxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1414
O




[(R)-((R)-2-(Hydroxymethyl)-4-morpholinobutoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1415
O




[(R)-((S)-2-(Hydroxymethyl)-4-morpholinobutoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1416
O




[(R)-((S)-4-Hydroxy-2-(2-morpholinoethyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1417
O




[(R)-((R)-4-Hydroxy-2-(2-morpholinoethyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1418
O




[(R)-(((S)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1419
O




[(R)-(((R)-4-Hydroxy-6-(4-methylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1420
O




[(R)-(((S)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1421
O




[(R)-(((R)-4-Hydroxy-6-(4-ethylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1422
O




[(R)-(((R)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1423
O




[(R)-(((S)-4-Hydroxy-6-(4-isopropylpiperazin-1- yl)hexyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1424
O




[(R)-(((S)-3-Hydroxymethyl-5-(4-methylpiperazin-1- yI)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1425
O




[(R)-(((R)-3-Hydroxymethyl-5-(4-methylpiperazin-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1426
O




[(R)-(((S)-3-Hydroxymethyl-5-(4-ethylpiperazin-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1427
O




[(R)-(((R)-3-Hydroxymethyl-5-(4-ethylpiperazin-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1428
O




[(R)-(((R)-3-Hydroxymethyl-5-(4-isopropylpiperazin-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1429
O




[(R)-(((S)-3-Hydroxymethyl-5-(4-isopropylpiperazin-1- yl)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1430
O




[(R)-(((R)-2-(Hydroxymethyl)-4-morpholinobutyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1431
O




[(R)-((S)-2-(Hydroxymethyl)-4-morpholinobutoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1432
O




[(R)-((S)-4-Hydroxy-2-(2-morpholinoethyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1433
O




[(R)-((R)-4-Hydroxy-2-(2-morpholinoethyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1434
O




[(R)-(((R)-4-Hydroxy-5-(neopentylamino)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1435
O




[(R)-(((S)-4-Hydroxy-5-(neopentylamino)pentyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1436
O




[(R)-(((S)-4-Hydroxy-3- ((neopentylamino)methyl)butyl)oxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1437
O




[(R)-((R)-4-Hydroxy-3- ((neopentylamino)methyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1438
O




[(R)-((S)-4-Hydroxy-2- ((neopentylamino)methyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1439
O




[(R)-((R)-4-Hydroxy-2- ((neopentylamino)methyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1440
O




[(R)-(((R)-4-Hydroxy-6-(neopentylamino)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1441
O




[(R)-(((S)-4-Hydroxy-6-(neopentylamino)hexyl)oxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1442
O




[(R)-(((R)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1443
O




[(R)-(((S)-3-(Hydroxymethyl)-5- (neopentylamino)pentyl)oxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1444
O




[(R)-((R)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1445
O




[(R)-((S)-4-Hydroxy-2-(2- (neopentylamino)ethyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1446
O




[(R)-(4-(N,N-Dimethylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1447
O




[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1448
O




[(R)-(4-(N-Isopropylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1449
O




[(R)-(4-(N-Isopropyl-N-methylamino)butoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1450
O




[(R)-(4-(N-Ethyl-N-isopropylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1451
O




[(R)-(4-(N-Isobutylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1452
O




[(R)-(4-(N-Isobutyl-N-methylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1453
O




[(R)-(4-(N-ethyl-N-isobutylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1454
O




[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1455
O




[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1456
O




[(R)-(4-(N-Methyl-N-neopentylamino)butoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1457
O




[(R)-(4-(N-Ethyl-N-neopentylamino)butoxy)methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1458
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1459
O




[(R)-(4-(N-Thiazolidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1460
O




[(R)-(4-(N-Oxazolidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1461
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1462
O




[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1463
O




[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1464
O




[(R)-(4-(N-Piperazinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1465
O




[(R)-(4-(4-Methyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1466
O




[(R)-(4-(4-Ethyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1467
O




[(R)-(4-(4-Propyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1468
O




[(R)-(4-(4-Isopropyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1469
O




[(R)-(4-(4-Isobutyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1470
O




[(R)-(4-(4-Neopentyl-N-piperazinyl)butoxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1471
O




[(R)-(4-(4-(2-Hydroxyethyl)-N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1472
O




[(R)-(4-(4-(2-Hydroxy-2-methylpropyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1473
O




[(R)-(4-(4-(3-Hydroxy-3-methylbutyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1474
O




[(R)-(4-(4-(4-Hydroxy-4-methylpentyl)-N- piperazinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1475
O




[(R)-(4-(4-(2-Methoxyethyl)-N-piperazinyl)butoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1476
O




[(R)-(4-(4-(2-Methoxy-2-methylpropyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1477
O




[(R)-(4-(4-(3-Methoxy-3-methylbutyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1478
O




[(R)-(4-(4-(4-Methoxy-4-methylpentyl)-N-piperazinyl) butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1479
O




[(R)-(4-Carboxybutoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1480
O




[(R)-(4-Carboxybutoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1481
O




[(R)-(4-Carboxybutoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1482
O




[(R)-(4-(Ethoxycarbonyl)butoxy)methyl-Sar]-3-[(γ-methoxy)- N-MeLeu]-4-cyclosporin


 


1483
O




[(R)-(5-Carboxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1484
O




[(R)-(5-Carboxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1485
O




[(R)-5-((Ethoxycarbonyl)pentyloxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1486
O




[(R)-(5-Hydroxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1487
O




[(R)-(5-Methoxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1488
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1489
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-potassium salt


 


1490
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-sodium salt


 


1491
O




[(R)-(4-Ethoxycarbonylpentyloxy)methyl-Sar]-3-[(γ- methoxy)-N-MeLeu]-4-cyclosporin


 


1492
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1493
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin-dipotassium salt


 


1494
O




[(R)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1495
O




[(R)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1496
O




[(R)-(6-Hydroxyhexyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1497
O




[(R)-(6-Methoxyhexyloxy)methyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


 


1498
O




[(R)-[(N-(2-Aminoethyl)carbamoyl)methoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1499
O




[(R)-[(N-(2-(Neopentylamino)ethyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1500
O




[(R)-[(N-(3-Aminopropyl)carbamoyl)methoxy]methyl [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1501
O




[(R)-[(N-(3-(Neopentylamino)propyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1502
O




[(R)-[(N-(4-Aminobutyl)carbamoyl)methoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1503
O




[(R)-[(N-(4-(Neopentylamino)butyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1504
O




[(R)-[(N-(5-Aminopentyl)carbamoyl)methoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1505
O




[(R)-[(N-(5-(Neopentylamino)pentyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1506
O




[(R)-[(N-(6-Aminohexyl)carbamoyl)methoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1507
O




[(R)-[(N-(6-(Neopentylamino)hexyl)carbamoyl)methoxy] methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1508
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1509
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl)ethoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1510
O




[(R)-[([HO-Gly-(D-Glu)6]carbamoyl)propoxy]methyl-Sar]-3- [(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1511
O




[(R)-((2-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]ethoxy) methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1512
O




[(R)-((3-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]propoxy) methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1513
O




[(R)-((4-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]butoxy) methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1514
O




[(R)-((5-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]pentyloxy) methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1515
O




[(R)-((6-[([HO-Gly-(D-Glu)6]carbamoyl)methoxy]hexyloxy) methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin


 


1516
O




[(R)-(4-Butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1517
O




[(R)-(5-Pentyloxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1518
O




[(R)-(6-Hexyloxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1519
O




[(R)-(7-Heptyloxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


 


1520
CH2
—NO2
[(R)-2-Nitroethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


1521
CH2
—NH2
[(R)-2-Aminoethyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4- cyclosporin


1522
CH2
—N(CH3)2
[(R)-2-(N,N-Dimethylamino)ethyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


1523
CH2
—N(CH2CH3)2
[(R)-2-(N,N-Diethylamino)ethyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


1524
CH2
—CH2N(CH3)2
[(R)-2-(N,N-Dimethylamino)propyl-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


1525
CH2
—(COOEt)2
[(R)-2,2-Di(ethoxycarbonyl)ethyl)-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin


1526
CH2
—(CH2OH)2
[(R)-2,2-Di(hydroxylmethyl)ethyl)-Sar]-3-[(γ-methoxy)-N- MeLeu]-4-cyclosporin
















TABLE 4













 










Ex.





No.
W
Ra
Name





1527
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1528
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin-potassium salt


 


1529
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin-sodium salt


 


1530
S




[(S)-(Ethoxycarbonylmethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1531
S




[(S)-(2-Hydroxyethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1532
S




[(S)-(2-Hydroxy-2,2-dimethylethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1533
S




[(S)-(2-(N-Isobutylamino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1534
S




[(S)-(2-(N-Isobutyl-N-methylamino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1535
S




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1536
S




[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1537
S




[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1538
S




[(S)-(2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1539
S




[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1540
S




[(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1541
S




[(S)-(3-Hydroxypropylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1542
S




[(S)-(3-Hydroxy-3-methylbutylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1543
S




[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1544
S




[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1545
S




[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1546
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1547
S




[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1548
S




[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4-cyclosporin


 


1549
S




[(S)-(3-(N-Methyl-N-neopentylamino)propylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1550
S




[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1551
S




[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1552
S




[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1553
S




[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1554
S




[(S)-(4-Hydroxybutylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1555
S




[(S)-(4-Hydroxy-4-methylpentylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1556
S




[(S)-(4-(N,N-Dimethylamino)butylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1557
S




[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1558
S




[(S)-(4-(N-Isobutylamino)butylthio)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1559
S




[(S)-(4-(N-Isobutyl-N-methylamino)butylthio)methyl-Sar]-3- [N-MeVal]-4-cyclosporin


 


1560
S




[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1561
S




[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1562
S




[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]- 3-[N-MeVal]-4-cyclosporin


 


1563
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1564
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1565
S




[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1566
S




[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1567
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1568
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-potassium salt


 


1569
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-sodium salt


 


1570
S




[(S)-(3-Ethoxycarbonylpropylthio)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1571
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1572
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-potassium salt


 


1573
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-sodium salt


 


1574
O




[(R)-((Ethoxycarbonyl)methoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1575
O




[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1576
O




[(R)-(2-Hydroxy-2-methylprpoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1577
O




[(R)-(2-(N-Isobutylamino)ethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1578
O




[(R)-(2-(N-Isobutyl-N-methylamino)ethoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1579
O




[(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1580
O




[(R)-(2-(N-Methyl-N-neopentylamino)ethoxy)methyl-Sar]-3- [N-MeVal]-4-cyclosporin


 


1581
O




[(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1582
O




[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1583
O




[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1584
O




[(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1585
O




[(R)-(3-Hydroxypropoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1586
O




[(R)-(3-Hydroxy-3-methylbutoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1587
O




[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1588
O




[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1589
O




[(R)-(3-(N-Isobutylamino)propoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1590
O




[(R)-(3-(N-Isobutyl-N-methylamino)propoxy)methyl-Sar]-3- [N-MeVal]-4-cyclosporin


 


1591
O




[(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1592
O




[(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1593
O




[(R)-(3-(N-Methyl-N-neopentylamino)propoxy)methyl-Sar]-3- [N-MeVal]-4-cyclosporin


 


1594
O




[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1595
O




[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1596
O




[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1597
O




[(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1598
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1599
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-potassium salt


 


1600
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin-sodium salt


 


1601
O




[(R)-(3-(Ethoxycarbonyl)propoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1602
O




[(R)-(4-Hydroxybutoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1603
O




[(R)-(4-Hydroxy-4-methylpentyloxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1604
O




[(R)-(4-(N,N-Dimethylamino)butoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1605
O




[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1606
O




[(R)-(4-(N-Isobutylamino)butoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin


 


1607
O




[(R)-(4-(N-Isobutyl-N-methylamino)butoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1608
O




[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1609
O




[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[N- MeVal]-4-cyclosporin


 


1610
O




[(R)-(4-(N-Methyl-N-neopentylamino)butoxy)methyl-Sar]-3- [N-MeVal]-4-cyclosporin


 


1611
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1612
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1613
O




[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[N-MeVal]-4- cyclosporin


 


1614
O




[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[N-MeVal]- 4-cyclosporin
















TABLE 5













 










Ex. 





No.
W
Ra
Name





1615
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1616
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1617
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1618
S




[(S)-(Ethoxycarbonylmethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1619
S




[(S)-(2-Hydroxyethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1620
S




[(S)-(2-Hydroxy-2-methylpropylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1621
S




[(S)-(2-(N-Isobutylamino)ethylthio)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1622
S




[(S)-(2-(N-Isobutyl-N-methylamino)ethylthio)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1623
S




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1624
S




[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1625
S




[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1626
S




[(S)-2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1627
S




[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1628
S




[(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1629
S




[(S)-(3-Hydroxypropylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1630
S




[(S)-(3-Hydroxy-3-methylbutylthio)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1631
S




[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1632
S




[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1633
S




[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1634
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1635
S




[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1636
S




[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1637
S




[(S)-(3-(N-Methyl-N-neopentylamino)propylthio)methyl-Sar]- 3-[N-MeIle]-4-cyclosporin


 


1638
S




[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1639
S




[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1640
S




[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1641
S




[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1642
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1643
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1644
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1645
S




[(S)-(3-Ethoxycarbonylpropylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1646
S




[(S)-(4-Hydroxybutylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1647
S




[(S)-(4-Hydroxy-4-methylpentylthio)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1648
S




[(S)-(4-(N,N-Dimethylamino)butylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1649
S




[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1650
S




[(S)-(4-(N-Isobutylamino)butylthio)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1651
S




[(S)-(4-(N-Isobutyl-N-methylamino)butylthio)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1652
S




[(S)-(4-(N,N-Diisobutyl-N-methylamino)butylthio)methyl- Sar]-3-[N-MeIle]-4-cyclosporin


 


1653
S




[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1654
S




[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]- 3-[N-MeIle]-4-cyclosporin


 


1655
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1656
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1657
S




[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1658
S




[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1659
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1660
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1661
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1662
S




[(S)-(4-Ethoxycarbonylpentylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1663
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1664
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-dipotassium salt


 


1665
S




[(S)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[N-MeIle]-4-cyclosporin


 


1666
S




[(S)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[N-MeIle]-4-cyclosporin


 


1667
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1668
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1669
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1670
O




[(R)-((Ethoxycarbonyl)methoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1671
O




[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1672
O




[(R)-(2-Hydroxy-2-methylpropoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1673
O




[(R)-(2-(N-Isobutylamino)ethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1674
O




[(R)-(2-(N-Isobutyl-N-methylamino)ethoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1675
O




[(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1676
O




[(R)-(2-(N-Methyl-N-neopentylamino)ethoxy)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1677
O




[(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1678
O




[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1679
O




[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1680
O




[(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1681
O




[(R)-(3-Hydroxypropoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1682
O




[(R)-(3-Hydroxy-3-methylbutoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1683
O




[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1684
O




[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[N- McIle]-4-cyclosporin


 


1685
O




[(R)-(3-(N-Isobutylamino)propoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1686
O




[(R)-(3-(N-Isobutyl-N-methylamino)propoxy)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1687
O




[(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1688
O




[(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1689
O




[(R)-(3-(N-Methyl-N-neopentylamino)propoxy)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1690
O




[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1691
O




[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1692
O




[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1693
O




[(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1694
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1695
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1696
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1697
O




[(R)-(3-(Ethoxycarbonyl)propoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1698
O




[(R)-(4-Hydroxybutoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1699
O




[(R)-(4-Hydroxy-4-methylpentyloxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1700
O




[(R)-(4-(N,N-Dimethylamino)butoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1701
O




[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1702
O




[(R)-(4-(N-Isobutylamino)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1703
O




[(R)-(4-(N-Isobutyl-N-methylamino)butoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1704
O




[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[N- MeIle]-4-cyclosporin


 


1705
O




[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1706
O




[(R)-(4-(N-Methyl-N-neopentylamino)butoxy)methyl-Sar]-3- [N-MeIle]-4-cyclosporin


 


1707
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1708
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1709
O




[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1710
O




[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[N-MeIle]- 4-cyclosporin


 


1711
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1712
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-potassium salt


 


1713
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-sodium salt


 


1714
O




[(R)-(4-Ethoxycarbonylpentyloxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1715
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin


 


1716
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[N-MeIle]-4- cyclosporin-dipotassium salt


 


1717
O




[(R)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[N-MeIle]-4-cyclosporin


 


1718
O




[(R)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[N-MeIle]-4-cyclosporin


 


1719
CH2
—NO2
[(R)-2-Nitroethyl-Sar]-3-[N-MeIle]-4-cyclosporin


1720
CH2
—NH2
[(R)-2-Aminoethyl-Sar]-3-[N-MeIle]-4-cyclosporin


1721
CH2
—N(CH3)2
[(R)-2-(N,N-Dimethylamino)ethyl-Sar]-3-[N-MeIle]-4-cyclosporin


1722
CH2
—N(CH2CH3)2
[(R)-2-(N,N-Diethylamino)ethyl-Sar]-3-[N-MeIle]-4-cyclosporin


1723
CH2
—CH2N(CH3)2
[(R)-2-(N,N-Dimethylamino)propyl-Sar]-3-[N-MeIle]-4-cyclosporin


1724
CH2
—(COOEt)2
[(R)-2,2-Di(ethoxycarbonyl)ethyl)-Sar]-3-[N-MeIle]-4-cyclosporin


1725
CH2
—(CH2OH)2
[(R)-2,2-Di(hydroxylmethyl)ethyl)-Sar]-3-[N-MeIle]-4-cyclosporin
















TABLE 6













 










Ex. 





No.
W
Ra
Name





1726
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1727
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-potassium salt


 


1728
S




[(S)-(Carboxymethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-sodium salt


 


1729
S




[(S)-(Ethoxycarbonylmethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1730
S




[(S)-(2-Hydroxyethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1731
S




[(S)-(2-Hydroxy-2-methylpropylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1732
S




[(S)-(2-(N-Isobutylamino)ethylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1733
S




[(S)-(2-(N-Isobutyl-N-methylamino)ethylthio)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1734
S




[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1735
S




[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1736
S




[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1737
S




[(S)-(2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1738
S




[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1739
S




[(S)-(2-(N-Thiomorpholino)ethylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeul-4-cyclosporin


 


1740
S




[(S)-(3-Hydroxypropylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1741
S




[(S)-(3-Hydroxy-3-methylbutylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1742
S




[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1743
S




[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1744
S




[(S)-(3-(N-Isobutylamino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1745
S




[(S)-(3-(N-Isobutyl-N-methylamino)propylthio)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1746
S




[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1747
S




[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1748
S




[(S)-(3-(N-Methyl-N-neopentylamino)propylthio)methyl-Sar]- 3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1749
S




[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1750
S




[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1751
S




[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1752
S




[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1753
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1754
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-potassium salt


 


1755
S




[(S)-(3-Carboxypropylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-sodium salt


 


1756
S




[(S)-(3-Ethoxycarbonylpropylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1757
S




[(S)-(4-Hydroxybutylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1758
S




[(S)-(4-Hydroxy-4-methylpentylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1759
S




[(S)-(4-(N,N-Dimethylamino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1760
S




[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1761
S




[(S)-(4-(N-Isobutylamino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1762
S




[(S)-(4-(N-Isobutyl-N-methylamino)butylthio)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1763
S




[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1764
S




[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1765
S




[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]- 3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1766
S




[(S)-(4-(N-Pyrrolidinyl)butylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1767
S




[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1768
S




[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1769
S




[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1770
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1771
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-potassium salt


 


1772
S




[(S)-(4-Carboxypentylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-sodium salt


 


1773
S




[(S)-(4-Ethoxycarbonylpentylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1774
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1775
S




[(S)-((4,4′-Dicarboxy)butylthio)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-dipotassium salt


 


1776
S




[(S)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1777
S




[(S)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutylthio)methyl- Sar]-3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1778
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-allyloxy)-NMeLeu]- 4-cyclosporin


 


1779
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-allyloxy)-NMeLeu]- 4-cyclosporin-potassium salt


 


1780
O




[(R)-(Carboxymethoxy)methyl-Sar]-3-[(γ-allyloxy)-NMeLeu]- 4-cyclosporin-sodium salt


 


1781
O




[(R)-((Ethoxycarbonyl)methoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1782
O




[(R)-(2-Hydroxyethoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1783
O




[(R)-(2-Hydroxy-2-methylpropoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1784
O




[(R)-(2-(N-Isobutylamino)ethoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1785
O




[(R)-(2-(N-Isobutyl-N-methylamino)ethoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1786
O




[(R)-(2-(N-Neopentylamino)ethoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1787
O




[(R)-(2-(N-Methyl-N-neopentylamino)ethoxy)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1788
O




[(R)-(2-(N-Pyrrolidinyl)ethoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1789
O




[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1790
O




[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1791
O




[(R)-(2-(N-Thiomorpholino)ethoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1792
O




[(R)-(3-Hydroxypropoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1793
O




[(R)-(3-Hydroxy-3-methylbutoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1794
O




[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1795
O




[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1796
O




[(R)-(3-(N-Isobutylamino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1797
O




[(R)-(3-(N-Isobutyl-N-methylamino)propoxy)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1798
O




[(R)-(3-(N,N-Diisobutylamino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1799
O




[(R)-(3-(N-Neopentylamino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1800
O




[(R)-(3-(N-Methyl-N-neopentylamino)propoxy)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1801
O




[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1802
O




[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1803
O




[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1804
O




[(R)-(3-(N-Thiomorpholino)propoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1805
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1806
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-potassium salt


 


1807
O




[(R)-(3-Carboxypropoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-sodium salt


 


1808
O




[(R)-(3-(Ethoxycarbonyl)propoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1809
O




[(R)-(4-Hydroxybutoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1810
O




[(R)-(4-Hydroxy-4-methylpentyloxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1811
O




[(R)-(4-(N,N-Dimethylamino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1812
O




[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1813
O




[(R)-(4-(N-Isobutylamino)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1814
O




[(R)-(4-(N-Isobutyl-N-methylamino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1815
O




[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1816
O




[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1817
O




[(R)-(4-(N-Methyl-N-neopentylamino)butoxy)methyl-Sar]-3- [(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1818
O




[(R)-(4-(N-Pyrrolidinyl)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1819
O




[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1820
O




[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1821
O




[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ- allyloxy)-NMeLeu]-4-cyclosporin


 


1822
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1823
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-potassium salt


 


1824
O




[(R)-(4-Carboxypentyloxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-sodium salt


 


1825
O




[(R)-(4-Ethoxycarbonylpentyloxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1826
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


 


1827
O




[(R)-((4,4′-Dicarboxy)butoxy)methyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin-dipotassium salt


 


1828
O




[(R)-((R)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1829
O




[(R)-((S)-3-Hydroxymethyl-4-ethoxycarbonybutoxy)methyl- Sar]-3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


 


1830
CH2
—NO2
[(R)-2-Nitroethyl-Sar]-3-[(γ-allyloxy)-NMeLeu]-4-cyclosporin


1831
CH2
—NH2
[(R)-2-Aminoethyl-Sar]-3-[(γ-allyloxy)-NMeLeu]-4- cyclosporin


1832
CH2
—N(CH3)2
[(R)-2-(N,N-Dimethylamino)ethyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


1833
CH2
—N(CH2CH3)2
[(R)-2-(N,N-Diethylamino)ethyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


1834
CH2
—CH2N(CH3)2
[(R)-2-(N,N-Dimethylamino)propyl-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


1835
CH2
—(COOEt)2
[(R)-2,2-Di(ethoxycarbonyl)ethyl)-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin


1836
CH2
—(CH2OH)2
[(R)-2,2-Di(hydroxylmethyl)ethyl)-Sar]-3-[(γ-allyloxy)- NMeLeu]-4-cyclosporin









Example 1837
Stability Testing of [(R)-3-(N,N-Dimethylamino)ethylthio-Sar]-3-[(γ-Hydroxy)-NMeLeu]-4-cyclosporin (SCY-635) and Cyclosporin Derivatives
Stability of Cyclosporin derivatives was evaluated in methanol at 65° C. and 50° C., and HPLC was used to monitor possible isomerization of these compounds. It was found that SCY-635 is not stable and can easily convert to its corresponding epimer, which is expected to have low or no anti-viral activity.










Epimerization of SCY-635* in MeOH at 65° C.








 









SCY-635's epimer %












Epimerization
2 hours
4 hours
6 hours
8 hours
10 hours





SCY-635 ⇄ SCY-635's epimer
24%
35%
39%
41%
43%





*SCY-635 was prepared according to a method described by: Evans M, et al., 2003, Bioorg. Med. Chem. Lett., 4, 4415-4419; Carry J, et al., 2004, Synlett. 2, 316-320; or U.S. Pat. No. 5,994,299 (each of which is incorporated herein by reference).
















Epimerization of SCY-635's epimer* in MeOH at 65° C.









SCY-635 %










Epimerization
3 hours
6 hours
10 hours





SCY-635's epimer   SCY-635
51%
58%
58%





*During the stability study, it was found that SCY-635 transformed into its epimer, which was separated as a pure compound. HPLC RT: 14.60 minutes (SCY-635) and: 15.01 minutes (its epimer) (C8 reverse phase column, 250 mm, acetonitrile/0.077% NH4OAc in water, operation temperature: 64° C.; Detector: 210 nm).






When the epimer was treated with MeOH at 65° C., it also was found that it partially transformed to SCY-635. At the endpoint of the equilibrium, this solution contained about 58% of SCY-635 and about 42% of epimer.







TABLE 7







Epimerization of [(R)-2-(N,N-dimethylamino)ethylthio-Sar]-3-cyclosporin in MeOH at 65° C.











Epimerization %












Compound
2 hours
4 hours
6 hours





 




~12%
~19%
~23%
















TABLE 8







Epimerization of [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin in MeOH at 65° C.









Epimerization % in MeOH at 65° C.












Compound
2 hours
4 hours
6 hours
8 hours
10 hours









0%
0%
0%
Less than 1%
~10%
















TABLE 9







Epimerization of [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-Methoxy)-NMeLeu]-4-cyclosporin in MeOH at 65° C.









Epimerization % in MeOH at 65° C.













Compound
2 hours
4 hours
10 hours
22 hours
30 hours
38 hours









0%
0%
0%
0%
0%
0%
















TABLE 10







Epimerization of Cyclosporin Derivatives in MeOH at 50° C.









Epimerization %










Compounds
29 hours
77 hours
125 hours









~26% 
~32% 
~35% 


 






0%
Less than 1%
~12% 


 






0%
0%
0%


 






0%
0%
0%


 






0%
0%
0%


 






~4% 
~10% 
~16% 


 






0%
0%
0%


 






0%
0%
0%


 






0%
0%
0%


 






0%
0%
0%
















TABLE 11







Epimerization of Cyclosporin Derivatives in MeOH at 50° C.-58° C.











Epimerization % after



Compound
168 hours










0%


 







0%


 







0%


 







0%


 







0%


 







0%


 







0%


 







0%


 







0%


 







0%


 







0%









Based on the isomerization data, the inventors suggest that the epimerization of SCY-635 occurs through the following reaction mechanism:







Thus, the two carbon side chain at position 3 of the sarcosine of cyclosporine contributes to the instability, because it can form a six-membered ring transition state, and stimulate the epimerization. Additionally, the epimerization is accelerated by the γ-hydroxyl group at the 4-position of leucine.
Accordingly, the inventors envisioned novel cyclosporine derivatives having enhanced stability while maintaining good cyclophilin binding activity. In particular, the inventors have surprisingly found that the masking the γ-hydroxyl group on leucine at position 4, elongating side carbon chain (e.g., with 3 carbons or higher), and/or substituting the amine terminal at position 3 with a bulky side chain can prevent or minimize the epimerization. Specially, when the methylene substituents are introduced on position-3, those analogs are very stable, and can prevent the epimerization.
Example 1838
Anti HCV Activity of Cyclosporin Derivatives
Anti-HCV activity of cyclosporine derivatives were evaluated in the HCV subgenomic replicon assay. The assay use the cell line ET (luc-ubi-neo/ET), which is a Huh7 human hepatoma cell line harboring an HCV replicon with a stable luciferase (Luc) reporter. HCV RNA replication was assessed by quantifying HCV replicon-derived luciferase activity. The antiviral activity of cyclosporine analogs were evaluated after drug treatment to derive EC50 and EC90 values by using the luciferase end point (Krieger, N., et al., 2001, J. Virol. 75, 4614-4624; Pietschmann, T., et al., 2002, J. Virol. 76, 4008-4021; each of which is incorporated herein by reference). Cytotoxicity was assessed in parallel.







TABLE 12







Testing results of certain representative compounds









Antiviral



activity


Compound
EC50 (μM)





Cyclosporine A
0.41


[N-MeIle]-4-cyclosporin (SDZ-NIM-811)
0.15


[N-MeVal]-4-cyclosporin (SDZ 220-384)
0.17


(S)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeIle]-4-
0.04


cyclosporin



(R)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeIle]-4-
1.87


cyclosporin



(S)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeVal]-4-
0.04


cyclosporin



(R)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeVal]-4-
3.66


cyclosporin



(S)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[N-MeVal]-4-
0.13


cyclosporin



(S)-2-(N-neo-Pentylamino)ethylthio-Sar]-3-cyclosporin
0.23


(R)-2-(N-neo-Pentylamino)ethylthio-Sar]-3-cyclosporin
3.09


(S)-2-(N-iso-Butyl-N-iso-propylamino)ethylthio-Sar]-3-
0.48


cyclosporin 



(R)-2-(N-iso-Butyl-N-iso-propylamino)ethylthio-Sar]-3-
4.65


cyclosporin 



(S)-2-(N-Diethylamino)ethylthio-Sar]-3-cyclosporin
0.16


[(S)-2-(N,N-Diethylamino)ethylthio-Sar]-3-
0.11


[(γ-Methylthio)methoxy-NMeLeu]-4-cyclosporin
















TABLE 13







Testing results of certain representative compounds









Antiviral



activity


Compound
EC50 (μM)





[N-MeVal]-4-cyclosporin (SDZ 220-384)
0.12


(S)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(γ-hydroxy)-N-
0.08


MeLeu]-4-cyclosporin (SCY-635)



[(S)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin



[(R)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-hydroxy)-N-
0.15


MeLeu]-4-dihydrocyclosporin



[(S)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-methoxy)-N-
0.06


MeLeu]-4-cyclosporin



(S)-3-(N,N-Diethylamino)propylthio-Sar]-3-[(γ-hydroxy)-N-
0.07


MeLeu]-4-cyclosporin



[(S)-(3-(N-Morpholino)propylthio-Sar]-3-[(γ-ethoxy)methoxy-
0.16


N-MeLeu]-4-cyclosporin



[(S)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[(γ-
0.13


methylthio)methoxy-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Morpholino)propylthio-Sar]-3-[(γ-
0.16


methylthio)methoxy-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Morpholino)propylthio-Sar]-3-[(γ-benzyloxy)-N-
0.28


MeLeu]-4-cyclosporin



[(S)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-(4-Methoxy)-
0.28


benzyloxy)-N-MeLeu]-4-cyclosporin



[(S)-3-(N-Morpholino)propylthio-Sar]-3-[(γ-allyloxy)-N-
0.15


MeLeu]-4-cyclosporin



[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-
0.03


hydroxy)-N-MeLeu]-4-cyclosporin (isomer B)



[(R)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-
2.12


Hydroxy)-N-MeLeu]-4-cyclosporin (isomer A)



[(γ-Methoxy)-N-MeLeu]-4-cyclosporin
0.18


[(γ-Methoxy)-N-MeLeu]-4-dihydrocyclosporin
0.35


[(γ-Methylthio)methoxy-N-MeLeu]-4-cyclospori
0.40


[γ-(2-Hydroxyethoxy)-N-MeLeu]-4-dihydrocyclosporin
0.43


[N-MeSer]-4-cyclosporin
0.56
















TABLE 14







Testing results of certain representative compounds









Antiviral activity


Compound
EC50 (μM)





[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[γ-(Hydroxy)-N-
0.05


MeLeu]-4-cyclosporin (isomer B)


[(R)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[γ-(Hydroxy)-N-
2.12


MeLeu]-4-cyclosporin (isomer A)


[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.03


NMeLeu]-4-cyclosporin (isomer B)


[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-
0.02


4-cyclosporin


[(S)-(2-(N-Piperidinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-
0.04


cyclosporin


[(S)-(2-(4-Methyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.03


NMeLeu]-4-cyclosporin


[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-
0.02


4-cyclosporin


[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.05


NMeLeu]-4-cyclosporin


[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.03


NMeLeu]-4-cyclosporin


[(S)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-
0.05


NMeLeu]-4-cyclosporin


[(S)-(2-(N-Isopropyl-N-methylamino)ethylthio)methyl-Sar]-3-[(γ-
0.04


hydroxy)-NMeLeu]-4-cyclosporin


[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-
0.02


NMeLeu]-4-cyclosporin


[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-
0.04


cyclosporin


[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-
0.02


Methylthio)methoxy-NMeLeu]-4-cyclosporin


[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-Ethoxy)methoxy-
0.02


NMeLeu]-4-cyclosporin


[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-
0.12


4-cyclosporin
















TABLE 15







Testing results of certain representative compounds









Antiviral



activity


Compound
EC50 (μM)





[N-MeIle]-4-cyclosporin (SDZ-NIM-811)
0.14


[N-MeVal]-4-cyclosporin (SDZ 220-384)
0.14


[(R)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(γ-hydroxy)-N-
0.12


MeLeu]-4-cyclosporin (SCY-635)



[D-N-MeAla]-3[N-EtVal]-4-cyclosporin (Debio-025)
0.07


[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-
0.09


hydroxy)-N-MeLeu]-4-cyclosporin (isomer B)



(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[γ-
0.13


(Hydroxy)-N-MeLeu]-4-cyclosporin (isomer B)



[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.06


N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Piperidinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.05


N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Piperidino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.08


N-MeLeu]-4-cyclosporin



[(S)-(2-(4-Methylpiperazino)ethylthio)methyl-Sar]-3-[(γ-
0.09


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.11


N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[(γ-
0.10


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-
0.05


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-
0.09


[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ-
0.11


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-
0.08


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Ethyl-N-isopropylamino)propylthio)methyl-Sar]-3-
0.06


[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Ethyl-N-isopropylamino)ethylthio)methyl-Sar]-3-
0.07


[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-
0.12


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Methyl-N-iso-propylamino)ethylthio)methyl-Sar]-
0.10


3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Isopropylamino)ethylthio)methyl-Sar]-3-[(γ-
0.19


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N,N-Diisobutylamino)ethylthio)methyl-Sar]-3-[(γ-
0.12


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-
0.06


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Ethyl-N-neopentylamino)ethylthio)methyl-Sar]-3-
0.06


[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Methyl-N-neopentylamino)ethylthio)methyl-Sar]-
0.07


3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin



[(R)-(Ethoxycarbonylmethoxy)methyl-Sar]-3-cyclosporin
0.18


[(R)-(3-(N, N-Diethylamino)propoxy)methyl-Sar]-3-
0.12


cyclosporin



[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-
0.13


cyclosporin



[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[(γ-
0.06


methoxy)-N-MeLeu]-4-cyclosporin



[(R)-(3-(N-Morpholino)propoxy)methyl-Sar]-3-[(γ-hydroxy)-
0.09


N-MeLeu]-4-cyclosporin



[(S)-3-(N,N-Diethylamino)propylthio-Sar]-3-[N-MeIle]-4-
0.08


cyclosporin



[(R)-(3-(N-Pyrrolidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-
0.22


N-MeLeu]-4-cyclosporin



[(S)-3-(N,N-Diethylamino)propylthio-Sar]-3-[N-MeVal]-4-
0.07


cyclosporin



[(S)-(3-(N-Morpholino)propylthio-Sar]-3-[N-MeVal]-4-
0.11


cyclosporin



[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[N-
0.14


MeVal]-4-cyclosporin



[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[N-
0.10


MeIle]-4-cyclosporin



[(R)-(2-(N,N-Diethylamino)ethoxy)methyl-Sar]-3-[N-MeIle]-
0.16


4-cyclosporin



[(R)-(3-(N-Piperidinyl)propoxy)methyl-Sar]-3-[(γ-hydroxy)-
0.15


N-MeLeu]-4-cyclosporin



[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-
0.15


cyclosporin



[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-
0.17


cyclosporin (isomer B)



[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-
0.16


cyclosporin (isomer B)



[(R)-(2-(N-Piperidinyl)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-
0.14


MeLeu]-4-cyclosporin



[(R)-(2-(N-Pyrrolidino)ethoxy)methyl-Sar]-3-[(γ-hydroxy)-N-
0.20


MeLeu]-4-cyclosporin



[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-3-[(γ-
0.10


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N,N-Dimethylamino)propylthio)methyl-Sar]-3-[(γ-
0.09


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N,N-Diethylamino)propylthio)methyl-Sar]-3-[(γ-
0.07


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N,N-Diethylamino)ethylthio)methyl-Sar]-3-[(γ-
0.09


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Pyrrolidinyl)ethylthio)methyl-Sar]-3-[(γ-methoxy)-
0.09


N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-3-[(γ-methoxy)-
0.11


N-MeLeu]-4-cyclosporin



[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-[(γ-
0.15


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-
0.10


methoxy)-N-MeLeu]-4-cyclosporin



[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-
0.18


hydroxy)-N-MeLeu]-4-cyclosporin



[(S)-(3-(N-Pyrrolidinyl)propylthio)methyl-Sar]-3-[(γ-
0.10


methoxy)-N-MeLeu]-4-cyclosporin



[(S)-[(3-(N-piperidino)propylthio)methyl-Sar]-3-[(γ-
0.06


methoxy)-N-MeLeu]-4-cyclosporin



[(R)-(2-(N,N-Dimethylamino)ethoxy)methyl-Sar]-3-[(γ-
0.24


hydroxy)-N-MeLeu]-4-cyclosporin



[(R)-(3-(N,N-Dimethylamino)propoxy)methyl-Sar]-3-[(γ-
0.26


hydroxy)-N-MeLeu]-4-cyclosporin



[(R)-(3-(N,N-Diethylamino)propoxy)methyl-Sar]-3-[(γ-
0.10


methoxy)-N-MeLeu]-4-cyclosporine



[(R)-(2-(N-Morpholino)ethoxy)methyl-Sar]-3-[(γ-methoxy)-
0.15


N-MeLeu]-4-cyclosporin
















TABLE 16







Testing results of certain representative compounds









Antiviral activity


Compound
EC50 (μM)





[(R)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-
0.11


cyclosporin (SCY-635)


[D-N-MeAla]-3-[N-EtVal]-4-cyclosporin (Debio-025)
0.05


[(S)-(2-(N-Neopentylamino)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin


[(S)-(2-(4-Ethyl-N-piperazinyl)ethylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.06


MeLeu]-4-cyclosporin


[(S)-(3-(N,N-Diisobutylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.04


MeLeu]-4-cyclosporin


[(S)-(3-(N-Neopentylamino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin


[(S)-(3-(N-Morpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.04


MeLeu]-4-cyclosporin


[(S)-(3-(N-Thiomorpholino)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin


[(S)-(3-(4-Methyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-
0.04


N-MeLeu]-4-cyclosporin


[(S)-(3-(4-Ethyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin


[(S)-(3-(4-N-n-Propyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-
0.05


hydroxy)-N-MeLeu]-4-cyclosporin


[(S)-(3-(4-N-Isopropyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-
0.05


hydroxy)-N-MeLeu]-4-cyclosporin


[(S)-(3-(4-N-Isobutyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-
0.05


hydroxy)-N-MeLeu]-4-cyclosporin


[(S)-(3-(4-N-Neopentyl-N-piperazinyl)propylthio)methyl-Sar]-3-[(γ-
0.06


hydroxy)-N-MeLeu]-4-cyclosporin


[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.07


MeLeu]-4-cyclosporin


[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.04


MeLeu]-4-cyclosporin


[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.04


MeLeu]-4-cyclosporin


[(S)-(4-hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-
0.02


cyclosporin


[(S)-(4-(2-(Diethylamino)ethoxy)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-
0.05


MeLeu]-4-cyclosporin









Example 1839
Anti HIV Activity of Cyclosporin Derivatives
Anti-HIV activity of cyclosporine derivatives were evaluated by cytoprotection assay in an acute infection model using CEM-SS cells and either HIV-1IIIB or HIV-1 RF. Antiviral activity was determined as a reduction in virus-caused cytopathic effects when compounds prevent virus replication. Cytoprotection and compound cytotoxicity were evaluated using the tetrazollium dye MTS (Promega) to calculate cell viability following virus infection after 6-day incubation (Zhou G., et al., 2011, J. Med. Chem. 27, 7220-31; which is incorporated herein by reference).







TABLE 17







Testing results of certain representative compounds


against HIV-1IIIB in CEM-SS cells (MTS Endpoint)









Antiviral activity


Compound
EC50 (nM)











AZT
9.0


[(S)-(2-(N,N-Dimethylamino)ethylthio)methyl-Sar]-
118.0


3-[(γ-Hydroxy)-NMeLeu]-4-cyclosporin (isomer B)


[(S)-(2-(N-Morpholino)ethylthio)methyl-Sar]-
94.9


3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin









Examples 1840
Inhibition of Mitochondrial Permeability Transition (MPT)
The effect of cyclosporine analogs on mitochondrial permeability transition (MPT) was determined by a modified mitochondrial swelling assay measured as an influx of Ca2+, published by J. Blattner et al., 2001, Analytical Biochem, 295, 220-226. Briefly, rat neuronal mitochondria in an ice-cold sucrose buffer were obtained after rat whole-body perfusion and a series of centrifugation. The total protein concentration in each sample batch was determined for standardization between assays. The mitochondrial swelling was induced by 100 micromolar of Calcium Chloride. Each compound (100 nM) was added to mitochondria 5 minutes before the addition of Ca.2+. The value of absorbance at the certain wavelength (620 nm) reflected the degree of mitochondrial swelling. The percentage of the swelling was calculated by comparing the absorbance in the present or absent compound of the interests.







TABLE 18







Inhibition of Mitochondrial Swelling









Mitochondrial



Swelling


Compounds
Relative %











Control
100


Cyclosporin A
68.7


[(S)-2-(N-Diethylamino)ethylthio-Sar]-3-[(γ-
52.4


methylthio)methoxy-N-MeLeu]-4-cyclosporin



[(S)-(2-(N-Diethylamino)ethylthio)methyl-Sar]-3-
55.7


[(γ-hydroxy)-N-MeLeu]-4-cyclosporin









In above assay, the results in mitochondrial swelling strongly indicate that cyclosporine analogs can penetrate the mitochondrial membrane and inhibit mitochondrial swelling.

## Claims

1. A compound of Formula (III):



or pharmaceutically acceptable salt thereof, wherein:
 represents a single bond or double bond;
W is O, S, or CH2;
Wherein R3 




or R3 is —(CH2)4— substituted by a substituent selected from the group consisting of NH2, NMe2, NEt2, NH(iso-butyl), NMe(iso-buty), NEt(iso-buty), N(iso-buty)2, NH(neopenty), NMe(neopentyl), NEt(neopentyl), N(iso-butyl)(neopentyl), N(neopentyl)2,




H, Me, Et, or;
and wherein R5 is H, (C1-C6)alkyl, (C2-C6)alkenyl, phenyl, benzyl, CH2—S—(C1-C6)alky, CH2—C—(C1-C6)alkyl, (C2-C6)alkylOH, or (C2-C6)alkylO(C1-C6)alkyl.

2. The compound of claim 1, wherein W is O.

3. The compound of claim 1, wherein W is S.

4. The compound of claim 1, wherein R3 is —(CH2)4— substituted by a subsitituent selected from the group consisting of NH2, NMe2, NEt2, NH(iso-butyl), NMe(iso-butyl), NEt(iso-butyl), N(iso-butyl)2, NH(neopentyl), NMe(neopentyl), NEt(neopentyl),

5. The compound of claim 1, wherein R3 is

6. The compound of claim 1, wherein R5 is H, (C1—C6)alkyl, (C2—C6)alkenyl, phenyl, benzyl, CH2—S—(C1—C6)alky, or CH2—O—(C1—C6)alkyl.

7. The compound of claim 1, wherein R3 is —(CH2)4— substituted by a substituent selected from the group consisting of NH2, NMe2, NEt2, NH(iso-butyl), NMe(iso-butyl), NEt(iso-butyl), N(iso-butyl)2, NH(neopentyl), NMe(neopentyl), NEt(neopentyl), and N(neopentyl).

8. The compound of claim 1, wherein R3 is

9. The compound is claim 1, wherein represents a double bond.

10. A compound of claim 1, wherein R3 is —(CH2)4— substituted by a substituent selected from the group consisting of

11. The compound of claim 1, wherein R3 is

12. A compound according to claim 1, selected from the group consisting of:
[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Methyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Ethyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Ethyl-N-Neopentylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Methyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Methyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Ethyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Ethyl-N-Neopentylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Morpholino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Thiomorpholino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Morpholino)butoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Thiomorpholino)butoxy)methyl-Sar]-3-[(γ-allyloxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N,N-Diethylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N,N-Diethylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N,N-Diisobutylamino)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N,N-Diisobutylamino)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(3-Hydroxylpropylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(3-Methoxypropylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-Methoxybutylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(5-Hydroxylpentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(5-Methoxypentylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(5-Hydroxylpentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(5-Methoxypentylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(S)-(4-(N-Piperidinyl)butylthio)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin,
[(R)-(4-(N-Piperidinyl)butoxy)methyl-Sar]-3-[(γ-methoxy)-N-MeLeu]-4-cyclosporin,
and
a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 having the following structure:















or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

15. A method for treating hepatitis C virus infection, hepatitis B virus infection, or HIV infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to claim 1.

16. A method for inhibiting a cyclophilin in a subject in need thereof, the method comprising administrating to said subject an effective cyclophilin-inhibiting amount of at least one compound according to claim 1.

17. A method for treating a disease mediated by cyclophilin in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to claim 1.

18. A compound of claim 1 having a structure selected from the group consisting of

19. A compound of claim 1, having the structure of



or a pharmaceutically acceptable salt thereof.

20. The method of claim 16, wherein the cyclophilin is ayclophilin A, B, or C.

21. The method of claim 16, wherein the cyclophilin is cyclophilin D.

22. The method of claim 17, wherein the cyclophilin is cyclophilin A, B, or C.

23. The method of claim 17, wherein the cyclophilin is cyclophilin D.

24. The compound of claim 1, wherein R5 is H or (C1-C6)alkyl.